WO2015123713A1 - Polyvinylpyrrolidone hybrid polymer having a backbone grafted with polyvinylpyrrolidone - Google Patents

Polyvinylpyrrolidone hybrid polymer having a backbone grafted with polyvinylpyrrolidone Download PDF

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WO2015123713A1
WO2015123713A1 PCT/AT2015/050049 AT2015050049W WO2015123713A1 WO 2015123713 A1 WO2015123713 A1 WO 2015123713A1 AT 2015050049 W AT2015050049 W AT 2015050049W WO 2015123713 A1 WO2015123713 A1 WO 2015123713A1
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polyvinylpyrrolidone
hybrid polymer
grafted
cio
polyphosphazene
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French (fr)
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Ian Teasdale
Oliver BRÜGGEMANN
Sandra ROTHEMUND
Helena HENKE
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Universität Linz
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    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08GMACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G81/00Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
    • C08G81/02Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • C08G81/024Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F283/00Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F26/00Homopolymers and 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
    • C08F26/06Homopolymers and 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 by a heterocyclic ring containing nitrogen
    • C08F26/10N-Vinyl-pyrrolidone
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08GMACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G79/00Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule
    • C08G79/02Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule a linkage containing phosphorus
    • C08G79/025Polyphosphazenes
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L87/00Compositions of unspecified macromolecular compounds, obtained otherwise than by polymerisation reactions only involving unsaturated carbon-to-carbon bonds
    • C08L87/005Block or graft polymers not provided for in groups C08L1/00 - C08L85/04
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2438/00Living radical polymerisation
    • C08F2438/03Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]

Definitions

  • the invention relates to a polyvinylpyrrolidone hybrid polymer having a polyvinylpyrrolidone grafted backbone.
  • Polyvinylpyrrolidone is mainly used in cosmetic and pharmaceutical fields, but is not biodegradable. As a result, high molecular weight polyvinylpyrrolidone is unsuitable for certain applications, such as the repeated intravenous administration of an active ingredient, and may also cause long-term biological and environmental problems. Although it is possible to use polyvinylpyrrolidone with a low molecular weight below the renal clearance (about 20 kDa), this limitation is unsatisfactory for many applications because higher molecular weights are essential to many polymeric carrier properties.
  • X is O, NH or S
  • the invention avoids the difficulties of the known polyvinylpyrrolidone hybrid polymers by polyvinylpyrrolidone oligomers having a low molecular weight (preferably between 200 and 2000 Da) are often bound to an inorganic backbone of polyphosphazene.
  • the resulting hybrid polymers have a predominant proportion of, for example, 95 to 99 mol% of polyvinylpyrrolidone, so that many of the chemical properties of the pure polyvinylpyrrolidone can be expected.
  • the backbone of polyphosphazene is hydrolytically unstable, whereby the hybrid polymers according to the invention are degraded in an aqueous environment to oligomeric polyvinylpyrrolidone and a pH neutral buffer solution of phosphates and ammonia.
  • polyphosphazene Since the polyphosphazene has two functional groups per repeat unit, it is not necessary to replace both functional groups by polyvinylpyrrolidone. This opens up a broad field for the use of Co substituents, which allow a large number of co-polymers with a wide range of degradation rates.
  • the basic structure of the hybrid polymers according to the invention offers the possibility of adjusting the rate of biodegradation of the polymers by incorporating a linker between the organic and inorganic components of the hybrid polymers.
  • the basis of these linkers can be advantageously formed by an amino acid.
  • CI 3 PNTMS can be subjected to a cationic living polymerization.
  • corresponding hybrid polymers product 3 are obtained according to the reaction scheme below.
  • n and m not only the molecular weight of the polymers but also the ratio of the organic and inorganic fractions to each other can be adjusted.
  • the upper limit for m and n will preferably be given as 1000, with particularly advantageous ratios resulting when the highest value is m 100 and n is 150. Even with low values of m, a high ratio of vinylpyrrolidone to phosphazene can be maintained, so that the many useful chemical properties of vinylpyrrolidone can be exploited.
  • the hydrolytic degradation rate of the hybrid polymers can be changed by incorporating a linker between the organic and inorganic components.
  • the insertion of an amino acid improves the rate of degradation of the hydrophilic phosphorases.
  • the insertion of a linker can be carried out, for example, according to the reaction scheme below and leads to the product 4.
  • R ' may preferably be selected from alanyl, valinyl, leucinyl, isoieucinyl, propynyl, phenylamino, tryptophanyl, ethioninyl, glycine I, serinyl, threoninyl, cysteine, tyrosinyl, aspartyl, glutainyl, aspartoyl, glutoyl, lysinyl However, it is not restricted to this group.
  • One of the two functional groups of the poly can also be substituted by a co-polymer according to the following reaction scheme, which also affects the rate of degradation.
  • co-polymers can be prepared, wherein, for example, a co-substitution with crosslinkable functional groups, such as vinyl, acryloyl and the like, leads to biodegradable hydrogels.
  • crosslinkable functional groups such as vinyl, acryloyl and the like
  • Exemplary Embodiment ⁇ -Hydroxylpolyvinylpyrrolidone (Product 1) Azobisisobutyronitrile (AIBN) (0.075 g, 0.45 mmol), CTA S-1-cyanoethyl-O-ethyl-xanthate (0.75 g, 3.96 mmol) and N-vinylpyrrolidone (NVP) (1.9.55 g, 175.9 mmol) were degassed with argon, heated and stirred in an oil bath at 60 ° C. for 6 h. The reaction mixture was then cooled to room temperature and precipitated in diethyl ether. The filtered white powder was dried under vacuum.
  • AIBN Azobisisobutyronitrile
  • CTA S-1-cyanoethyl-O-ethyl-xanthate (0.75 g, 3.96 mmol
  • N-vinylpyrrolidone N-vinylpyrrolidone
  • the monomer CI 3 P N-SiMe 3 (0.45 g, 2.01 mmol) and the initiator PCI 5 (0.02 g, 0.08 mmol) were dissolved in a glove box in CH 2 Cl 2 and at room temperature touched. After 12 h, the solvent was removed in vacuo. The resulting poly (dichlorophosphazene) was used for macromolecular substitution without further purification.
  • the poly (dichlorophosphazene) precursor (product 2) was prepared in a glove box at room temperature.
  • the monomer CI 3 PNSiMe 3 (0.05 g, 0.22 mmol) and the initiator PCI 5 (1, 9 mg, 0.01 mmol) were separately dissolved in water. dissolved free CH 2 Cl 2 and then added the mixtures and stirred overnight.
  • the deprotection of the polyvinylpyrrolidone-Val-boc polymer was reported in
  • the degradation behavior of the polymers was assessed by the determination of the inorganic phosphates by monitoring by UV-Vis spectroscopy.
  • the polymers were incubated in TRIS buffer (pH 7.4) or acidified H2O (pH 2, improved degradation conditions) at a concentration of 4 mg / ml at 37 ° C during the analysis time. Aliquots of the decomposing medium were taken at regular time intervals and mixed with a reagent solution of ammonium molybdate, ascorbic acid, sulfuric acid and potassium antimonyl tartrate. A UV-Vis analysis of the mixtures was carried out after 15 min of the incubation time at 885 nm.
  • the concentration of phosphates was from a Calculated calibration curve using potassium dihydrogen phosphate and given as a percentage of the theoretical amount of phosphate that can be solved by the polymer backbone. In the drawing, the percentage phosphate decrease over the degradation time is shown. Curve 1, drawn in full line, illustrates the degradation rate in a TRIS buffer at pH 7.4. In comparison, according to the dash-dotted curve 2, significantly improved mining conditions result when the hybrid polymer is exposed to pH 2 acidified water.

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  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

The aim of the invention is to obtain a polyvinylpyrrolidone hybrid polymer having a backbone grafted with polyvinylpyrrolidone. To achieve said aim, it is proposed that the polyvinylpyrrolidone is grafted to a polyphosphazene according to structural formula (I).

Description

Polvvinylpyrrolidon-Hvbridpolvmer mit einem mit Polvvinylpyrrolidon gepfropften Rückgrat  Polvvinylpyrrolidone hybrid polymer having a polvvinylpyrrolidone grafted backbone
Technisches Gebiet Technical area
Die Erfindung bezieht sich auf ein Polyvinylpyrrolidon-Hybridpolymer mit einem mit Polyvinylpyrrolidon gepfropften Rückgrat. The invention relates to a polyvinylpyrrolidone hybrid polymer having a polyvinylpyrrolidone grafted backbone.
Stand der Technik State of the art
Polyvinylpyrrolidon wird vor allem in kosmetischen und pharmazeutischen Bereichen eingesetzt, ist aber biologisch nicht abbaubar. Dadurch wird Polyvinylpyrrolidon mit hohem Molekulargewicht für bestimmte Anwendungen, beispielsweise zur wiederholten intravenösen Verabreichung eines Wirkstoffs, ungeeignet und kann darüber hinaus biologische und umwelttechnische Langzeitprobleme verursachen. Obwohl es möglich ist, Polyvinylpyrrolidon mit einem niedrigen Molekulargewicht unterhalb der renalen Clearance (ca. 20 kDa) einzusetzen, ist diese Begrenzung für viele Anwendungsfälle unbefriedigend, weil höhere Molekulargewich- te wesentlich für viele Eigenschaften polymerer Träger sind. Polyvinylpyrrolidone is mainly used in cosmetic and pharmaceutical fields, but is not biodegradable. As a result, high molecular weight polyvinylpyrrolidone is unsuitable for certain applications, such as the repeated intravenous administration of an active ingredient, and may also cause long-term biological and environmental problems. Although it is possible to use polyvinylpyrrolidone with a low molecular weight below the renal clearance (about 20 kDa), this limitation is unsatisfactory for many applications because higher molecular weights are essential to many polymeric carrier properties.
Darstellung der Erfindung Presentation of the invention
Der Erfindung liegt somit die Aufgabe zugrunde, ein Polyvinylpyrrolidon- Hybridpolymer anzugeben, das nicht nur biologisch abbaubar ist, sondern auch die Schwierigkeiten vermeidet, die sich bei einem Polyvinylpyrrolidon mit einem hohen Molekulargewicht ergeben. Ausgehend von einem Polyvinylpyrrolidon-Hybridpolymer der eingangs geschilderten Art löst die Erfindung die gestellte Aufgabe dadurch, dass das Polyvinylpyrro- lidon an ein Polyphosphazen gemäß der Strukturformel It is therefore an object of the invention to provide a polyvinylpyrrolidone hybrid polymer which is not only biodegradable but also avoids the difficulties associated with a high molecular weight polyvinylpyrrolidone. Starting from a polyvinylpyrrolidone hybrid polymer of the type described above, the invention achieves the stated object in that the polyvinylpyrrolidone to a polyphosphazene according to the structural formula
Figure imgf000004_0001
gepfropft ist, wobei
Figure imgf000004_0001
being grafted, being
X für O, NH oder S steht, X is O, NH or S,
R1 aus einer (Ci bis C 0)-Alkyl, (Ci bis Ci0)-Alkenyl, (Ci bis Ci0)-Alkynyl, (Ci bis Cio)-Alkoxy, (Ci bis Cio)-Alkenoxy, (Ci bis Cio)-Acyl, Cycloalkyl, Cycloalkenyl, A- ryl, Arylalkyl, Arylalkenyl, (Ci bis Cio)-Heteroalkyl, (Ci bis Cio)-Heteroalkenyl, (Ci bis Ci0)-Heteroalkynyl, (Ci bis Ci0)-Heteroalkoxy, (Ci bis Ci0)-Heteroalkenoxy, (Ci bis Ci0)-Heteroacyl, Heterocycloalkyl, Heterocycloalkenyl, Heteroaryl, Heteroa- rylalkenyl, Heteroarylalkyl und Polyalkylenoxid umfassenden Gruppe ausgewählt ist, R1 of a (Ci to C 0) alkyl, (Ci to Ci 0) alkenyl, (Ci to Ci 0) alkynyl, (Ci to Cio) alkoxy, (Ci to Cio) alkenoxy, (Ci to Cio ) acyl, cycloalkyl, cycloalkenyl, A- ryl, arylalkyl, arylalkenyl, (Ci to Cio) heteroalkyl, (Ci to Cio) -Heteroalkenyl, (Ci to Ci 0) -Heteroalkynyl, (Ci to Ci 0) heteroalkoxy, (Ci to Ci 0) -Heteroalkenoxy, (Ci to Ci 0) is selected -Heteroacyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroaromatics rylalkenyl, heteroarylalkyl and polyalkylene oxide group comprising
R2 entweder für das über R1 gepfropfte Polyvinylpyrrolidon steht oder aus einer Alkyl, Alkenyl, Alkinyl, Alkoxy, Alkenoxy, Acyl, Cycloalkyl, Cycloalkenyl, Aryl, A- rylalkyl, Arylalkenyl, Heteroalkyl, Heteroalkenyl, Heteroalkinyl, Heteroalkoxy, Hete- roalkenoxy, Heteroacyl, Heterocycloalkyl, Heterocycloalkenyl, Heteroaryl, Heteroa- rykalkenyl, Heteroarylalkyl, Polyalkylenoxide, Acryloyl, Styryl, Cinnamyl, Vinyles- ter, Vinylcarbonat, Aminosäure, Aminosäureester und Depsipeptid umfassenden Gruppe ausgewählt ist und wobei gilt m = 1 bis 10000 und n = 3 bis 10000. Die Erfindung umgeht die Schwierigkeiten der bekannten Polyvinylpyrrolidon- Hybridpolymere, indem Polyvinylpyrrolidon-Oligomere mit einem niedrigen Molekulargewicht (vorzugsweise zwischen 200 und 2000 Da) vielfach an ein anorgani- sches Rückgrat aus Polyphosphazen gebunden werden. Die erhaltenen Hybridpolymere haben einen überwiegenden Anteil von beispielsweise 95 bis 99 mol% an Polyvinylpyrrolidon, sodass viele der chemischen Eigenschaften des reinen Po- lyvinylpyrrolidons erwartet werden können. Außerdem ist das Rückgrat aus Polyphosphazen hydrolytisch instabil, wodurch die erfindungsgemäßen Hybridpolyme- re in einer wässrigen Umgebung zu oligomerem Polyvinylpyrrolidon und einer pH neutralen Pufferlösung aus Phosphaten und Ammoniak abgebaut werden. R 2 is either the polyvinylpyrrolidone grafted via R 1, or is an alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkoxy, heteroalkenoxy, heteroacyl, Heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylkenyl, heteroarylalkyl, polyalkyleneoxides, acryloyl, styryl, cinnamyl, vinylester, vinylcarbonate, amino acid, amino acid esters and depsipeptide, and wherein m = 1 to 10,000 and n = 3 to 10,000. The invention avoids the difficulties of the known polyvinylpyrrolidone hybrid polymers by polyvinylpyrrolidone oligomers having a low molecular weight (preferably between 200 and 2000 Da) are often bound to an inorganic backbone of polyphosphazene. The resulting hybrid polymers have a predominant proportion of, for example, 95 to 99 mol% of polyvinylpyrrolidone, so that many of the chemical properties of the pure polyvinylpyrrolidone can be expected. In addition, the backbone of polyphosphazene is hydrolytically unstable, whereby the hybrid polymers according to the invention are degraded in an aqueous environment to oligomeric polyvinylpyrrolidone and a pH neutral buffer solution of phosphates and ammonia.
Da das Polyphosphazen zwei funktionale Gruppen je Wiederholungseinheit aufweist, müssen nicht beide funktionalen Gruppen durch Polyvinylpyrrolidon substituiert werden. Damit eröffnet sich ein weites Gebiet zum Einsatz von Co- Substituenten, die eine große Anzahl von Co-Polymeren mit einem weiten Bereich der Abbaurate ermöglichen. Since the polyphosphazene has two functional groups per repeat unit, it is not necessary to replace both functional groups by polyvinylpyrrolidone. This opens up a broad field for the use of Co substituents, which allow a large number of co-polymers with a wide range of degradation rates.
Des Weiteren bietet die Grundstruktur der erfindungsgemäßen Hybridpolymere die Möglichkeit, die Geschwindigkeit des biologischen Abbaus der Polymere durch Einfügen eines Linkers zwischen den organischen und anorganischen Komponen- ten der Hybridpolymere einzustellen. Die Basis dieser Linker kann vorteilhaft durch eine Aminosäure gebildet werden. Furthermore, the basic structure of the hybrid polymers according to the invention offers the possibility of adjusting the rate of biodegradation of the polymers by incorporating a linker between the organic and inorganic components of the hybrid polymers. The basis of these linkers can be advantageously formed by an amino acid.
Um in einfacher weise Polyvinylpyrrolidon-Oligomere mit monofunktionalen Endgruppen (Produkt 1 ) herstellen zu können, ist es bekannt, Vinylpyrrolidon einer RAFT Polymerisation, also einer speziellen Form einer kontrollierten freien radika- lischen Polymerisation, gemäß dem nachstehend skizzierten Verfahren anzuwenden. In order to be able to produce polyvinylpyrrolidone oligomers with monofunctional end groups (product 1) in a simple manner, it is known to use vinylpyrrolidone in a RAFT polymerization, ie a specific form of controlled free radical polymerization, according to the process outlined below.
Figure imgf000006_0001
Figure imgf000006_0001
Zur Herstellung von Poly(dichlorphosphazen) (Produkt 2) als Ausgangsprodukt für das Polyphosphazen-Rückgrat kann CI3PNTMS einer kationischen lebenden Polymerisation unterworfen werden. Durch das Ankoppeln der nucleophilen Endgruppe der monofunktionalen Polyvinylpyrrolidon-Oligomere (Produkt 1 ) an das Polyphosphazen-Rückgrat werden entsprechende Hybridpolymere (Produkt 3) gemäß dem nachfolgenden Reaktionsschema erhalten. For the preparation of poly (dichlorophosphazene) (product 2) as starting material for the polyphosphazene backbone, CI 3 PNTMS can be subjected to a cationic living polymerization. By coupling the nucleophilic end group of the monofunctional polyvinylpyrrolidone oligomers (product 1) to the polyphosphazene backbone, corresponding hybrid polymers (product 3) are obtained according to the reaction scheme below.
Figure imgf000006_0002
Figure imgf000006_0002
Durch eine Variation von n und m kann nicht nur das Molekulargewicht der Polymere, sondern auch das Verhältnis der organischen und anorganischen Anteile zueinander eingestellt werden. Die Obergrenze für m und n wird bevorzugt mit 1000 angegeben werden, wobei sich besonders vorteilhafte Verhältnisse ergeben, wenn der höchste Wert für m 100 und für n 150 beträgt. Selbst mit niedrigen Werten von m kann ein hohes Verhältnis von Vinylpyrrolidon zu Phosphazen eingehalten werden, sodass die vielen nützlichen chemischen Eigenschaften von Vinylpyrrolidon genützt werden können. Wie bereits ausgeführt wurde, kann die hydrolytische Abbaurate der Hybridpolymere durch das Einfügen eines Linkers zwischen den organischen und anorganischen Komponenten geändert werden. So verbessert das Einfügen einer Aminosäure die Abbaurate der hydrophilen Po!yphosphazene. Das Einfügen eines Linkers kann beispielsweise nach dem nachstehenden Reaktionsschema erfolgen und führt zum Produkt 4. By a variation of n and m, not only the molecular weight of the polymers but also the ratio of the organic and inorganic fractions to each other can be adjusted. The upper limit for m and n will preferably be given as 1000, with particularly advantageous ratios resulting when the highest value is m 100 and n is 150. Even with low values of m, a high ratio of vinylpyrrolidone to phosphazene can be maintained, so that the many useful chemical properties of vinylpyrrolidone can be exploited. As already stated, the hydrolytic degradation rate of the hybrid polymers can be changed by incorporating a linker between the organic and inorganic components. Thus, the insertion of an amino acid improves the rate of degradation of the hydrophilic phosphorases. The insertion of a linker can be carried out, for example, according to the reaction scheme below and leads to the product 4.
Figure imgf000007_0001
Figure imgf000007_0001
1. DCC, DMAP,CH2CI2 r.t, 24 h 1. DCC, DMAP, CH 2 Cl 2 rt, 24 h
2. TFA, CH2CI2 2. TFA, CH 2 Cl 2
Figure imgf000007_0002
Figure imgf000007_0002
R' kann dabei vorzugsweise aus einer Alanyl, Vaiinyl, Leucinyl, isoieucinyl, Proii- nyl, Pheny!a!aninyl, Tryptophanyl, ethioninyi, Glycin l, Serinyl, Threoninyl, Cys- teinyi, Tyrosinyl, AsparaginyL Glutainyl, Aspartoyl, Glutaoyl, Lysinyl, Ärgininyl und Histidinyl enthaltenden Gruppe ausgewählt sein, ist allerdings nicht auf diese Gruppe beschränkt. R 'may preferably be selected from alanyl, valinyl, leucinyl, isoieucinyl, propynyl, phenylamino, tryptophanyl, ethioninyl, glycine I, serinyl, threoninyl, cysteine, tyrosinyl, aspartyl, glutainyl, aspartoyl, glutoyl, lysinyl However, it is not restricted to this group.
Eine der beiden funktionellen Gruppen des Poly(dichlorphosphazens) kann auch durch ein Co-Polymer entsprechend dem folgenden Reaktionsschema substituiert werden, was sich ebenfalls auf die Abbaurate auswirkt.
Figure imgf000008_0001
One of the two functional groups of the poly (dichlorophosphazene) can also be substituted by a co-polymer according to the following reaction scheme, which also affects the rate of degradation.
Figure imgf000008_0001
2 Damit können vielfältige Co-Polymere hergestellt werden, wobei beispielsweise eine Co-Substitution mit zur Vernetzung fähigen funktionalen Gruppen, wie Vinyl, Acryloyl und dgl., zu bioabbaubaren Hydrogelen führt.  Thus, a variety of co-polymers can be prepared, wherein, for example, a co-substitution with crosslinkable functional groups, such as vinyl, acryloyl and the like, leads to biodegradable hydrogels.
Ausführungsbeispiel ω-Hydroxylpolyvinylpyrrolidon (Produkt 1 ) Azobisisobutyronitril (AIBN) (0,075 g, 0,45 mmol), CTA S-1 -Cyanoethyl-O- ethyl-xanthat (0.75 g, 3,96 mmol) und N-Vinylpyrrolidon (NVP) (1 9,55 g, 175,9 mmol) wurden mit Argon entgast, erwärmt und in einem Ölbad bei 60 QC während 6 h gerührt. Das Reaktionsgemisch wurde dann auf Raumtemperatur gekühlt und in Diethylether gefällt. Das ausgefilterte weiße Pulver wurde unter Vakuum getrocknet. Das Polymer wurde dann in deionisiertem Wasser H20 (5 ml) gelöst und bei 40 QC für 1 6 h gerührt. Die Lösung wurde dann gemeinsam mit Toluen unter Vakuum verdampft, in THF gelöst und in Diethylether gefällt. Das Pulver wurde gefiltert und unter Vakuum getrocknet, um ein weißes, hygroskopisches Pulver zu erhalten. Ausbeute: 7,6 g (39 %), 1H NMR (300 MHz, D2O, δ): 3,6 (br, 1 H), 3,3 (br, 2H), 2,4 (br, 1 H), 2,3 (br, 2H), 2,0 (br, 2.8H) 1 ,7 (br, 2H), 1 ,27 (s, 0.7H) ppm. Exemplary Embodiment ω-Hydroxylpolyvinylpyrrolidone (Product 1) Azobisisobutyronitrile (AIBN) (0.075 g, 0.45 mmol), CTA S-1-cyanoethyl-O-ethyl-xanthate (0.75 g, 3.96 mmol) and N-vinylpyrrolidone (NVP) (1.9.55 g, 175.9 mmol) were degassed with argon, heated and stirred in an oil bath at 60 ° C. for 6 h. The reaction mixture was then cooled to room temperature and precipitated in diethyl ether. The filtered white powder was dried under vacuum. The polymer was then dissolved in deionized water H 2 O (5 mL) and stirred at 40 ° C for 1 h. The solution was then coevaporated with toluene under vacuum, dissolved in THF and precipitated in diethyl ether. The powder was filtered and dried under vacuum to obtain a white, hygroscopic powder. Yield: 7.6 g (39%), 1 H NMR (300 MHz, D 2 O, δ): 3.6 (br, 1H), 3.3 (br, 2H), 2.4 (br, 1 H), 2.3 (br, 2H), 2.0 (br, 2.8H) 1, 7 (br, 2H), 1, 27 (s, 0.7H) ppm.
Poly(dichlorophosphazen) (Produkt 2) Poly (dichlorophosphazene) (product 2)
Das Monomer CI3P=N-SiMe3 (0,45 g, 2,01 mmol) und der Initiator PCI5 (0,02 g, 0,08 mmol) wurden in einer Glovebox in CH2CI2 gelöst und bei Raumtemperatur gerührt. Nach 12 h wurde das Lösungsmittel unter Vakuum entfernt. Das erhaltene Poly(dichlorophosphazen) wurde zur makromolekularen Substitution ohne weitere Reinigung genützt. The monomer CI 3 P = N-SiMe 3 (0.45 g, 2.01 mmol) and the initiator PCI 5 (0.02 g, 0.08 mmol) were dissolved in a glove box in CH 2 Cl 2 and at room temperature touched. After 12 h, the solvent was removed in vacuo. The resulting poly (dichlorophosphazene) was used for macromolecular substitution without further purification.
Quantitative Ausbeute: 31 P NMR (121 MHz, CDCI3, δ): -18 ppm. Polyphosphazen-Polyvinylpyrrolidon Hybridpolymer (Produkt 3) Es wurde eine Suspension von Natriumhydrid (60 % in Mineralöl) (0,2 g, 5,0 mmol) in THF hergestellt und ω-Hydroxylpolyvinylpyrrolidon (Produkt 1 ) (3,5 g, 5,2 mmol) hinzugefügt. Das Reaktionsgemisch wurde für 1 h bei Raumtemperatur gerührt, bevor in THF (5 ml) gelöstes Poly(dichlorphosphazen) (Produkt 2) hinzugefügt und die Umsetzung für weitere 24 h bei Raumtemperatur gerührt wurde. Das Reaktionsgemisch wurde gefiltert und das Lösungsmittel unter Vakuum entfernt. Das gefilterte Reaktionsgemisch wurde mittels Dialyse gegen H2O (24 h) und dann gegen Ethanol (48 h) gereinigt. Quantitative yield: 31 P NMR (121 MHz, CDCl 3 , δ): -18 ppm. Polyphosphazene-Polyvinylpyrrolidone Hybrid Polymer (Product 3) A suspension of sodium hydride (60% in mineral oil) (0.2 g, 5.0 mmol) in THF was prepared and ω-hydroxylpolyvinylpyrrolidone (product 1) (3.5 g, 5, 2 mmol) was added. The reaction mixture was stirred for 1 h at room temperature before adding poly (dichlorophosphazene) (product 2) dissolved in THF (5 mL) and stirring the reaction for an additional 24 h at room temperature. The reaction mixture was filtered and the solvent removed under vacuum. The filtered reaction mixture was purified by dialysis against H 2 O (24 h) and then against ethanol (48 h).
Ausbeute: 2,8 g (85 %). 1 H NMR (300 MHz, D2O, δ): 3,6 (br, 1 H), 3,3 (br, 2H), 2,4 (br, 1 H), 2,3 (br, 2H), 2,0 (br, 2.8H) 1 ,7 (br, 2H), 1 ,27 (s, 0,7H) ppm; 31 P NMR (121 MHz, D2O, δ): -7,5 ppm; SEC: Mn = 90 8001 g/mol, Mw = 102 600 g/mol, Mw / Mn = 1 ,2. Yield: 2.8 g (85%). 1 H NMR (300 MHz, D 2 O, δ): 3.6 (br, 1H), 3.3 (br, 2H), 2.4 (br, 1H), 2.3 (br, 2H ), 2.0 (br, 2.8H) 1, 7 (br, 2H), 1, 27 (s, 0.7H) ppm; 31 P NMR (121 MHz, D 2 O, δ): -7.5 ppm; SEC: M n = 90,8001 g / mol, M w = 102,600 g / mol, M w / M n = 1, 2.
Polyphosphazen-Polyvinylpyrrolidon Hybridpolymer (Produkt 4) Polyphosphazene-Polyvinylpyrrolidone Hybrid Polymer (Product 4)
Eine Mischung aus Boc-Val-OH (0,266 g, 1 ,1 eq) und DMAP (0,014 g, 0,1 eq) wurden in CH2CI2 gelöst. ω-Hydroxylpolyvinylpyrrolidon (Produkt 1 ) (2 g, 1 ,1 mmol) wurde ebenfalls in CH2CI2 gelöst und der Lösung zugefügt. Das Reaktionsgemisch wurde auf 0 °C abgekühlt und DCC (0,275 g, 1 ,2 eq) in CH2CI2 hinzugefügt. Die Lösung wurde bei 0 °C für 30 min gerührt. Das Eisbad wurde entfernt und die Lösung bei Raumtemperatur für 24 h gerührt. Die Lösung wurde gefiltert, das Lösungsmittel unter Vakuum reduziert und die Lösung wiederholt zweimal in Diet- hylether gefällt. Der Poly(dichlorophosphazen)-Vorläufer (Produkt 2) wurde in einer Glovebox bei Raumtemperatur vorbereitet. Das Monomer CI3PNSiMe3 (0,05 g, 0,22 mmol) und der Initiator PCI5 (1 ,9 mg, 0,01 mmol) wurden separat in wasser- freiem CH2CI2 gelöst und dann die Mischungen hinzugefügt und über Nacht gerührt. Die Entschützung des Polyvinylpyrrolidon-Val-boc-Polymers wurde in A mixture of Boc-Val-OH (0.266 g, 1.1 eq) and DMAP (0.014 g, 0.1 eq) were dissolved in CH 2 Cl 2 . ω-Hydroxylpolyvinylpyrrolidone (product 1) (2 g, 1.1 mmol) was also dissolved in CH 2 Cl 2 and added to the solution. The reaction mixture was cooled to 0 ° C and DCC (0.275 g, 1.2 eq) in CH 2 Cl 2 added. The solution was stirred at 0 ° C for 30 min. The ice bath was removed and the solution stirred at room temperature for 24 h. The solution was filtered, the solvent was reduced under vacuum and the solution was precipitated repeatedly in diethyl ether twice. The poly (dichlorophosphazene) precursor (product 2) was prepared in a glove box at room temperature. The monomer CI 3 PNSiMe 3 (0.05 g, 0.22 mmol) and the initiator PCI 5 (1, 9 mg, 0.01 mmol) were separately dissolved in water. dissolved free CH 2 Cl 2 and then added the mixtures and stirred overnight. The deprotection of the polyvinylpyrrolidone-Val-boc polymer was reported in
CH2CI2 durchgeführt: TFA = 2 : 1 . Die Lösung wurde für 1 h gerührt, das Lösungsmittel unter Vakuum entfernt und das Produkt zweimal in Diethylether gefällt. Das erhaltene Polyvinylpyrrolidon-Val-NH2 (1 ,06 g, 0,56 mmol) wurde in THF und Et3N (0,06 g, 1 eq) gelöst und die Poly(dichlorophosphazen)-Vorläuferlösung hinzugefügt, wonach die Mischung für 24 h gerührt wurde. Die Lösung wurde gefiltert und das Lösungsmittel unter Vakuum entfernt. Das Polymer wurde durch Dialyse (12 kDa Cutoff) in Ethanol für 120 h gereinigt. Das Lösungsmittel wurde unter Vakuum entfernt, das Polymer in CH2CI2 gelöst und in Diethylether gefällt, um im Lösungsmittel eingekapselte Reste zu entfernen. CH2CI2 performed: TFA = 2: 1. The solution was stirred for 1 h, the solvent removed under vacuum and the product precipitated twice in diethyl ether. The resulting polyvinylpyrrolidone-Val-NH 2 (1.06 g, 0.56 mmol) was dissolved in THF and Et 3 N (0.06 g, 1 eq) and the poly (dichlorophosphazene) precursor solution added, after which the mixture was stirred for Was stirred for 24 h. The solution was filtered and the solvent removed under vacuum. The polymer was purified by dialysis (12 kDa cutoff) in ethanol for 120 h. The solvent was removed under vacuum, the polymer was dissolved in CH 2 Cl 2 and precipitated in diethyl ether to remove residues encapsulated in the solvent.
Ausbeute: 0,28 g (33 %), 1H NMR (300 MHz, D2O, δ): 0,90 (b, 6H), 1 ,32 (b, 17H), 1 ,58 (b, 31 H), 1 ,71 (b, 75H), 2,00 (b, 133H), 2,27 (b, 77H), 2,39 (b, 46H), 3,28 (b, 1 13H), 3,60 (b, 53H) 3,76 (b, 15H) ppm. Yield: 0.28 g (33%), 1 H NMR (300 MHz, D 2 O, δ): 0.90 (b, 6H), 1, 32 (b, 17H), 1, 58 (b, 31 H), 1, 71 (b, 75H), 2.00 (b, 133H), 2.27 (b, 77H), 2.39 (b, 46H), 3.28 (b, 1 13H), 3 , 60 (b, 53H) 3.76 (b, 15H) ppm.
Kurze Beschreibung der Zeichnung Short description of the drawing
In der Zeichnung ist das Abbauverhalten erfindungsgemäßer Hybridpolymere anhand der zeitlichen Phosphatabnahme bei unterschiedlichen Abbaubedingungen veranschaulicht. In the drawing, the degradation behavior of inventive hybrid polymers is illustrated by the temporal phosphate decrease at different mining conditions.
Weg zur Ausführung der Erfindung Way to carry out the invention
Das Abbauverhalten der Polymere wurde anhand der Bestimmung der anorganischen Phosphate durch eine Überwachung mittels UV-Vis Spektroskopie beurteilt. Die Polymere wurden in TRIS-Puffer (pH 7,4) oder angesäuertem H2O (pH 2, ver- besserte Abbaubedingungen) in einer Konzentration von 4 mg/ml bei 37 °C während der Analysezeit inkubiert. Aliquote Anteile des Abbaumediums wurden in regelmäßigen Zeitintervallen genommen und mit einer Reagenzlösung aus Ammo- niummolybdat, Ascorbinsäure, Schwefelsäure und Kaliumantimonyltartrat gemischt. Eine UV-Vis Analyse der Mischungen wurde nach 15 min der Inkubations- zeit bei 885 nm durchgeführt. Die Konzentration der Phosphate wurde aus einer Eichkurve unter Verwendung von Kaliumdihydrogenphosphat berechnet und als Prozentsatz der theoretischen Phosphatmenge angegeben, die von der Polymerhauptkette gelöst werden kann. In der Zeichnung ist die prozentuale Phosphatabnahme über der Abbauzeit dargestellt. Die in einer vollen Linie gezeichnete Kurve 1 veranschaulicht die Abbaurate in einer TRIS-Puffersubstanz bei einem pH Wert von 7,4. Im Vergleich dazu ergeben sich gemäß der strichpunktiert dargestellten Kurve 2 erheblich verbesserte Abbaubedingungen, wenn das Hybridpolymer angesäuertem Wasser mit einem pH Wert von 2 ausgesetzt wird. The degradation behavior of the polymers was assessed by the determination of the inorganic phosphates by monitoring by UV-Vis spectroscopy. The polymers were incubated in TRIS buffer (pH 7.4) or acidified H2O (pH 2, improved degradation conditions) at a concentration of 4 mg / ml at 37 ° C during the analysis time. Aliquots of the decomposing medium were taken at regular time intervals and mixed with a reagent solution of ammonium molybdate, ascorbic acid, sulfuric acid and potassium antimonyl tartrate. A UV-Vis analysis of the mixtures was carried out after 15 min of the incubation time at 885 nm. The concentration of phosphates was from a Calculated calibration curve using potassium dihydrogen phosphate and given as a percentage of the theoretical amount of phosphate that can be solved by the polymer backbone. In the drawing, the percentage phosphate decrease over the degradation time is shown. Curve 1, drawn in full line, illustrates the degradation rate in a TRIS buffer at pH 7.4. In comparison, according to the dash-dotted curve 2, significantly improved mining conditions result when the hybrid polymer is exposed to pH 2 acidified water.

Claims

Patentansprüche claims
1. Polyvinylpyrrolidon-Hybridpolymer mit einem mit Polyvinylpyrrolidon gepfropften Rückgrat, dadurch gekennzeichnet, dass das Polyvinylpyrrolidon an ein Polyphosphazen gemäß der Strukturformel A polyvinylpyrrolidone hybrid polymer having a polyvinylpyrrolidone grafted backbone, characterized in that the polyvinylpyrrolidone is attached to a polyphosphazene according to the structural formula
Figure imgf000012_0001
gepfropft ist, wobei X für O, NH oder S steht,
Figure imgf000012_0001
grafted, where X is O, NH or S,
Ri aus einer (Ci bis Ci0)-Alkyl, (Ci bis Ci0)-Alkenyl, (Ci bis Ci0)-Alkynyl, (Ci bis Ci0)-Alkoxy, (Ci bis Ci0)-Alkenoxy, (Ci bis Ci0)-Acyl, Cycloalkyl, Cycloalkenyl, A- ryl, Arylalkyl, Arylalkenyl, (Ci bis Ci0)-Heteroalkyl, (Ci bis Ci0)-Heteroalkenyl, (Ci bis Cio)-Heteroalkynyl, (Ci bis Cio)-Heteroalkoxy, (Ci bis Cio)-Heteroalkenoxy, (Ci bis Cio)-Heteroacyl, Heterocycloalkyl, Heterocycloalkenyl, Heteroaryl, Heteroa- rylalkenyl, Heteroarylalkyl und Polyalkylenoxid umfassenden Gruppe ausgewählt ist, Ri from a (Ci to Ci 0 ) -alkyl, (Ci to Ci 0 ) -alkenyl, (Ci to Ci 0 ) -alkynyl, (Ci to Ci 0 ) -alkoxy, (Ci to Ci 0 ) -alkenoxy, (Ci to Ci 0) acyl, cycloalkyl, cycloalkenyl, A- ryl, arylalkyl, arylalkenyl, (Ci to Ci 0) heteroalkyl, (Ci to Ci 0) -Heteroalkenyl, (Ci to Cio) -Heteroalkynyl, (Ci to Cio) Heteroalkoxy, (Ci to Cio) -Heteroalkenoxy, (Ci to Cio) -Heteroacyl, Heterocycloalkyl, Heterocycloalkenyl, Heteroaryl, Heteroarylalkenyl, Heteroarylalkyl and Polyalkylenoxid comprising group is selected,
R2 entweder für das über R1 gepropfte Polyvinylpyrrolidon steht oder aus einer Al- kyl, Alkenyl, Alkinyl, Alkoxy, Alkenoxy, Acyl, Cycloalkyl, Cycloalkenyl, Aryl, Arylalkyl, Arylalkenyl, Heteroalkyl, Heteroalkenyl, Heteroalkinyl, Heteroalkoxy, Heteroal- kenoxy, Heteroacyl, Heterocycloalkyl, Heterocycloalkenyl, Heteroaryl, Heteroa- rykalkenyl, Heteroarylalkyl, Polyalkylenoxide, Acryloyl, Styryl, Cinnamyl, Vinyles- ter, Vinylcarbonat, Aminosäure, Aminosäureester und Depsipeptid umfassenden Gruppe ausgewählt ist und wobei gilt m = 1 bis 10000 und n = 3 bis 10000. R 2 is either the polyvinylpyrrolidone grafted via R 1 or is an alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkoxy, heteroalkhenoxy, Heteroacyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylkenyl, heteroarylalkyl, polyalkyleneoxides, acryloyl, styryl, cinnamyl, vinyles- ter, vinyl carbonate, amino acid, amino acid ester and depsipeptide-comprising group and wherein m = 1 to 10,000 and n = 3 to 10,000.
2. Polyvinylpyrrolidon-Hybridpolymer nach Anspruch 1 , dadurch gekennzeichnet, dass die Werte für m zwischen 1 und 1000 und für n zwischen 3 und 1000 lie- gen. 2. A polyvinylpyrrolidone hybrid polymer according to claim 1, characterized in that the values for m are between 1 and 1000 and for n between 3 and 1000.
3. Polyvinylpyrrolidon-Hybridpolymer nach Anspruch 2, dadurch gekennzeichnet, dass die Werte für m zwischen 1 und 100 und für n zwischen 3 und 150 liegen. A polyvinylpyrrolidone hybrid polymer according to claim 2, characterized in that the values for m are between 1 and 100 and for n between 3 and 150.
4. Polyvinylpyrrolidon-Hybridpolymer nach Anspruch einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass das Polyvinylpyrrolidon über Linker auf der4. polyvinylpyrrolidone hybrid polymer according to claim any one of claims 1 to 3, characterized in that the polyvinylpyrrolidone via linker on the
Basis einer Aminosäure an das Polyphosphazen gepfropft ist. Base of an amino acid to which polyphosphazene is grafted.
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CN113739524A (en) * 2021-08-04 2021-12-03 徐州恒世食品有限公司 Food additive drying device

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FR2510128A1 (en) * 1981-07-21 1983-01-28 Inst Mondial Phosphate Fireproof polymer, pref. polystyrene, compsn. - contg. poly:phosphazene homopolymer or grafted by the polymer
WO2006113274A1 (en) * 2005-04-15 2006-10-26 Parallel Solutions, Inc. Biodegradable polyphosphazenes containing pyrrolidone side groups
US20140030320A1 (en) * 2002-11-21 2014-01-30 Alexander Andrianov Biodegradable Polyphosphazenes Containing Pyrrolidone Side Groups

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JP3541894B2 (en) * 1994-02-18 2004-07-14 日本化薬株式会社 Temperature-responsive hydrogel
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FR2510128A1 (en) * 1981-07-21 1983-01-28 Inst Mondial Phosphate Fireproof polymer, pref. polystyrene, compsn. - contg. poly:phosphazene homopolymer or grafted by the polymer
US20140030320A1 (en) * 2002-11-21 2014-01-30 Alexander Andrianov Biodegradable Polyphosphazenes Containing Pyrrolidone Side Groups
WO2006113274A1 (en) * 2005-04-15 2006-10-26 Parallel Solutions, Inc. Biodegradable polyphosphazenes containing pyrrolidone side groups

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Publication number Priority date Publication date Assignee Title
CN113739524A (en) * 2021-08-04 2021-12-03 徐州恒世食品有限公司 Food additive drying device

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