AT515480A1 - A polyvinylpyrrolidone hybrid polymer having a polyvinylpyrrolidone grafted backbone - Google Patents

Abstract

In order to obtain a polyvinylpyrrolidone hybrid polymer having a backbone grafted with polyvinylpyrrolidone, it is proposed that the polyvinylpyrrolidone be grafted to a polyphosphazene according to the structural formula.

Description

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 renal clearance (about 20 kDa), this limitation is unsatisfactory for many applications because higher molecular weights are essential to many polymeric carrier properties.

It is therefore an object of the present 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 solves the stated object in that the polyvinylpyrrolidone to a polyphosphazene according to the structural formula

wherein X is O, NH or S, R1 is a (Ci to Ci0) alkyl, (Ci to Ci0) alkenyl, (Ci to Ci0) alkynyl, (Ci to Cio) alkoxy, (Ci to Ci0) -alkenoxy, (Ci to Ci0) acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, (Ci to Ci0) -Heteroalkyl, (Ci to C-i0) -Heteroalkenyl, (Ci to Cio) -Heteroalkynyl, (Ci to Ci0) -Heteroalkoxy, (Ci to Ci0) -Heteroalkenoxy, (Ci to Cio) -Heteroacyl, Heterocycloalkyl, Heterocycloalkenyl, Heteroaryl, Heteroarylalkynyl, Heteroarylalkyl and Polyalkylenoxid selected group, R2 either for the over R1 grafted Polyvinylpyrrolidon is or is an alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkoxy, heteroalkene-oxy, heteroacyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarykalke-nyl, Heteroarylalkyl, polyalkyleneoxides, acryloyl, styryl, cinnamyl, vinylester, vinylcarbonate, amino acid, amine is selected from the group comprising acid ester and depsipeptide, and where 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.

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.

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.

In order to be able to produce polyvinylpyrrolidone oligomers with monofunctional end groups (product 1) in a simple manner, it is known to apply vinylpyrrolidone to a RAFT polymerization, ie a specific form of controlled free radical polymerization, according to the process outlined below.

For the preparation of poly (dichlorophosphazene) (product 2) as starting material for the polyphosphazene backbone CI3PNTMS can be subjected to a cationic living poly merization. Coupling of the nucleophilic end group of the monofunctional polyvinylpyrrolidone oligomers (product 1) to the polyphosphazene backbone yields corresponding hybrid polymers (product 3) according to the reaction scheme below.

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 degradation rate of the hydrophilic polyphosphazenes. 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 Aianyi, Vaiinyl, Leucinyl, Isoieucinyi, Proiinyl, Phenyialanänyl, Tryptophanyl, Methioninyl, Glycinyl, Serinyl, Tbreoniny !, Gysteinyl, Tyrosinyi, Asparaginyi, Giutainyi, Aspartoyi, Giutaoyl, Lysinyl, Argininyl and Histidi-nyl Selected group, however, is not limited to this group.

One of the two functional groups of the poly (dichlorophosphazene) can also be substituted by a go-polymer according to the following reaction scheme, which also affects the rate of degradation.

Thus, a variety of co-polymers can be prepared, wherein, for example, a co-substitution with crosslinkable functional groups, such as vinyl, acrylolyl and the like, leads to biodegradable hydrogels.

Exemplary Embodiment ω-Hydroxylpolyvinylpyrrolidone (Product 1)

Azobisisobutyronitrile (AIBN) (0.075g, 0.45mmol), CTA S-1-cyanoethyl-O-ethyl-xanthate (0.75g, 3.96mmol) and N-vinylpyrrolidone (NVP) (19.55g, 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 QC for 16 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%), 1H NMR (300 MHz, D20, 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.

Poly (dichlorophosphazene) (product 2)

The monomer CI3P = N-SiMe3 (0.45 g, 2.01 mmol) and the initiator PCI5 (0.02 g, 0.08 mmol) were dissolved in a glove box in CH 2 Cl 2 and stirred at room temperature. After 12 h, the solvent was removed in vacuo. The resulting poly (di-chlorophosphazene) was used for macromolecular substitution without further purification.

Quantitative yield: 31P 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 poly (dichlorophosphazene) (product 2) dissolved in THF (5 ml) was added and the reaction was stirred for a further 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).

Yield: 2.8 g (85%). 1H NMR (300 MHz, D20, 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, 31P NMR (121 MHz, D20, δ): -7.5 ppm; SEC: Mn = 90,8001 g / mol, Mw = 102,600 g / mol, Mw / Mn = 1.2.

Polyphosphazene-Polyvinylpyrrolidone Hybrid Polymer (Product 4)

A mixture of Boc-Val-OH (0.266 g, 1.1 eq) and DMAP (0.014 g, 0.1 eq) was 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 reduced under vacuum and the solution repeatedly precipitated twice in diethyl ether. The poly (dichlorophosphazene) precursor (product 2) was prepared in a glove box at room temperature. The monomer CI3PNSiMe3 (0.05 g, 0.22 mmol) and the initiator PCI5 (1.9 mg, 0.01 mmol) were separately dissolved in anhydrous CH 2 Cl 2 and then the mixtures were added and stirred overnight. Deprotection of the polyvinylpyrrolidone-Val-boc polymer was performed in CH 2 Cl 2: 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 allowed to stand for 24 h h was stirred. 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.

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, 31H), 1 , 71 (b, 75H), 2.00 (b, 133H), 2.27 (b, 77H), 2.39 (b, 46H), 3.28 (b, 113H), 3.60 (b, 53H) 3.76 (b, 15H) ppm.

In the drawing, the degradation behavior of inventive hybrid polymers is illustrated by the temporal phosphate decrease at different mining conditions.

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 H 2 O (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 minutes of incubation at 885 nm. The concentration of phosphates was calculated from a calibration curve using potassium dihydrogen phosphate and reported as a percentage of the theoretical amount of phosphate that can be released from 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 (4)

Patent Attorneys Dipl.-Ing. Helmut Hübscher Dipl.-Ing. Karl Winfried Hellmich Spittelwiese 4, 4020 Linz (39622) II Claims 1. A polyvinylpyrrolidone hybrid polymer having a polyvinylpyrrolidone grafted backbone, characterized in that the polyvinylpyrrolidone is grafted to a poly-phosphazene according to the structural formula, wherein X is O, NH or S, R 1 is a (Ci to Ci0) alkyl, (Ci to Ci0) alkenyl, (Ci to Ci0) alkynyl, (Ci to Cio) alkoxy, (Ci to Ci0) - Alkenoxy, (Ci to Ci0) acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, (Ci to C-i0) -Heteroalkyl, (Ci to Ci0) -Heteroalkenyl, (Ci to Cio) -Heteroalkynyl, (Ci to Ci0 ) Heteroalkoxy, (Ci to Ci0) heteroalkenoxy, (Ci to Cio) heteroacyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, Heteroarylalke-nyl, heteroarylalkyl and polyalkylene oxide selected group, R2 is either the Ri grafted polyvinylpyrrolidone or from a Alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, A-rylalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkoxy, heteroalkenoxy, heteroacyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarykalkenyl, heteroarylalkyl, polyalkylene oxides, acryloyl, Styryl, cinnamyl, vinyl ester, vinyl carbonate, amino acid, amino acid ester and Dep sipeptide group is selected and where m = 1 to 10,000 and n = 3 to 10,000. 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. 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. A polyvinylpyrrolidone hybrid polymer according to any one of claims 1 to 3, characterized in that the polyvinylpyrrolidone is grafted via linkers based on an amino acid to the polyphosphazene. Linz, on 24 February 2014 University of Linz by: / Dl Karl Winfried Hellmich / (electronically signed)