Patent Application
20080319132
The invention under consideration relates to cross-linked, preferably biodegradable polyester urethanes with shape memory properties.
Biodegradable, covalent polymer networks with shape memory properties are usually obtained by means of free radical polymerization of, e.g., macrodimethacrylates. This method of production comprises a total of three steps: synthesis of macrodiols, methacrylation of the terminal groups and radical cross-linking.
The radical reaction mechanism is subject to a random process in which the microscopic structure of the cross-link points can be regulated only to a limited degree, so that structural heterogeneities can arise in the networks. Furthermore, with a chain reaction of that type, regulation and checking of the reaction is difficult, so that even if the starting materials in the network itself are very uniform, widely varying areas may be present, e.g., areas having a high cross-link density and areas having a lower cross-link density. This affects the use of materials of this type in some application areas, however. At the same time, such heterogeneities can also lead to variability in the physical properties.
The object of the invention under consideration is, therefore, to provide a new material and accompanying method for production with which the disadvantages of the state of the art can be overcome.
The object described above was solved by means of the polyurethane network according to Claim 1, as well as by means of the method defined in Claim 10. Preferred embodiments are specified in the sub-claims.
In order to avoid structural heterogeneities in the networks, the invention under consideration provides a novel system of amorphous polymer networks comprising one or several segments with shape memory properties. The networks are preferably composed of biodegradable and biocompatible components and they open up the possibility for use in the medical domain. The systemic character of the materials allows the thermal and mechanical properties, as well as the decomposition behavior, to be adjusted in a specific manner. In particular, the invention under consideration makes it possible to produce polyphase amorphous networks.
In contrast to the already developed biodegradable, covalent polymer networks with shape memory properties, which are obtained by means of free radical polymerization of, for example, macro-dimethacrylates, the invention under consideration calls for the use of a different method of production, namely polyaddition. In this process, a total of only two synthesis steps are necessary: synthesis of macrotriols or macrotetrols and polyaddition.
The networks according to the invention are based on star-shaped prepolymers with hydroxyl terminal groups, which are produced using known methods. This procedure makes it possible to produce structurally uniform networks (particularly even on a larger scale). By means of starting the production with multifunctional prepolymers, it is possible to ensure a very high degree of homogeneity of the networks, because the essential parameters of the networks can be specified just by the comparably low-molecular parent compounds as a result of the number of possible coupling points and the chain lengths of the prepolymers, which simplifies the control. At the same time, the cross-link points themselves are also already pre-shaped, which further facilitates the control.
The networks according to the invention comprise multifunctional constitutional units (derived from the abovementioned prepolymers), preferably trifunctional and/or tetrafunctional constitutional units, each of which preferably has a hydroxyfunctionality at the reactive ends or an equivalent grouping before the production of the network. The production of the network then takes place by reaction with a suitable diisocyanate or another suitable compound, preferably with a slight excess of diisocyanate.
The multifunctional constitutional units (prepolymers) comprise a central unit, which corresponds to the later cross-link points in the network. This central unit is preferably derived from suitable low-molecular multifunctional compounds, preferably with three or more hydroxyl groups, in particular, three to five and, more preferably, three or four hydroxyl groups. Suitable examples are pentaerythritol and 1,1,1-tris(hydroxymethyl)ethane. An appropriate number of prepolymer chains (corresponding, for example, to the number of hydroxyl groups) is bound to this central unit, wherein these chains preferably comprise monomer units bound by ester bonds and/or monomer units bound by ether bonds. Preferred examples are chains on the basis of lactic acid, caprolactone, dioxanone, glycolic acid and/or ethylene glycol or propylene glycol.
Preferred in this case are, in particular, chains of lactic acid (D or L or DL), optionally in combination with one of the other abovementioned acid constitutional units (as block copolymers or as statistical copolymers, wherein statistical copolymers are preferred). Alternatively, the chains comprise segments from the acid constitutional units (in the possible combinations mentioned above), together with segments from the ether constitutional units, wherein a combination with a polypropylene glycol segment is particularly preferred here. Preferably, such constitutional units possess two segments in each chain: a polyester segment and a polyether segment (particularly polypropylene glycol), wherein it is preferred for the polyether segment to be provided at the central unit, with the polyester segment affixed thereto, so that the chain ends are formed by the polyester segment.
The prepolymers normally have a number-average molecular weight (determined by GPS) of from 1,000 to 20,000 g/mol, preferably from 2,500 to 15,000 g/mol, particularly from 5,000 to 12,000 g/mol and furthermore preferably from 8,000 to 11,000 g/mol. In the case of prepolymers with segments of polyether units, the segments of polyether units preferably have a number-average molecular weight of from 1,000 to 6,000, and the polyester segments coupled thereto have a number-average molecular weight of from 1,000 to 12,000 g/mol, so that these prepolymers altogether again have a number-average molecular weight as described above.
Because prepolymers of this type can be produced by means of easily controlled methods, the prepolymers used in accordance with the invention preferably have a relatively large degree of homogeneity (PD), preferably in the range of from 1 to 2, particularly from 1 to 1.5. A good degree of homogeneity of this type also gives the networks according to the invention a good degree of homogeneity.
It is particularly preferred if the prepolymers have lactic acid units (lactate units). If further acid constitutional units are present, the lactate units preferably account for the greater portion of the acid units in the polyester segment. For the other abovementioned acid constitutional units, preferred proportions, in addition to lactate units, are as follows:
The prepolymers constructed as described above are reacted into the networks according to the invention by a polyaddition reaction. In this process, the reaction with the diisocyanates results in a chain linkage to the hydroxyl groups at the ends of the multifunctional prepolymers, so that the chains are then connected via diurethane units. Because of the hydrolysis sensitivity of the individual segments, this results in the development of a network that can be biodegradable, particularly in the physiological area. The selection of the components for the prepolymers furthermore particularly also allows the production of amorphous networks. In particular, the use of lactic acid (preferably DL form) and the use of atactic polypropylene glycol allow the production of completely amorphous networks.
In this process, the decomposition behaviour can be controlled by means of the proportion of individual monomers. Glycolate units, caprolactone units and dioxanone units generally delay the decomposition reaction.
Furthermore, the mechanical property profile of the network can also be controlled by means of the chain length and the respective proportion of monomers. Low molar masses of the prepolymers normally lead to networks with a high cross-link density, which can possibly have low mechanical stabilities, however. In return, the swelling capacity of such networks is limited.
The introduction of glycolate units, caprolactone units and/or dioxanone units furthermore allows control of the transition temperature and therefore the switch temperature for the shape memory effect (the shape memory effect is already extensively described in the state of the art; in this context, therefore, reference is merely made to the already existing literature, e.g., further patent applications made by the Mnemoscience company). In this way, desired switch temperatures can be selectively adjusted for an application.
The prepolymers according to the invention additionally also allow the production of phase-segregated networks, which is advantageous for some application areas. The following strategies lend themselves to the production of such phase-segregated networks.
Preferred acrylate monomers for option 4. are ethyl acrylate, butyl acrylate, hexyl acrylate and hydroxyethyl acrylate, as well as the corresponding methacrylates. The total mass proportion in the resulting IPN for these monomers preferably amounts to from 1 to 35% by mass, more strongly preferred from 8 to 25% by mass. Hydroxyethyl acrylate particularly allows an adjustment of the hydrophilicity of the IPN.
Preferred networks according to the invention are as follows:
The networks according to the invention can possess additional constituents, such as filling substances, biologically active substances, colouring substances, diagnostics, etc. The use of such additional constituents depends on the particular purpose.
FIG. A shows the glass temperature of the polyurethane networks (Type 1) with oligo[(rac-lactate)-co-glycolate] segments having various segment lengths.
FIG. B illustrates the restoration behaviour (shape memory effect) of a previously elongated network (Type 1) with oligo[(rac-lactate)-co-glycolate] segments in the heating process.
FIG. C shows the glass temperature of the polyurethane networks (Type 1) with oligo(lactate-co-hydroxycaproate) and oligo(lactate-hydroxyethoxy acetate) segments with variable lactate content.
FIG. D illustrates the restoration behavior (shape memory effect) of several polyurethane networks (Type 1) from FIG. C in the heating process.
FIG. E represents the thermal properties of the multiphase polymer networks (Type 1) with oligo(propylene glycol) and oligo(lactate-co-glycolate) segments.
FIG. F is a schematic depiction of the fixation of a pre-IPN by the subsequent cross-linking of the additional component (Type III).
FIG. G shows the swelling capability of an IPN (Type IV) in water with a variable proportion of 2(hydroxyethyl) acrylate.
The networks according to the invention can be simply obtained by means of the reaction of the prepolymers with diisocyanate in solution, e.g., in dichloromethane, and subsequent drying (Types 1 and II). In the production of the IPN with a second network of acrylate monomers, the network according to the invention is swollen in monomers after the production, whereupon the cross-linking of the monomers (Type IV) follows. In the case of the IPN with a second network of polypropylene glycol macromonomers, the network according to the invention is produced in the presence of the macromonomers (in solution, as described above), which are subsequently cross-linked (Type III). In principle, mass polymerization is also possible, i.e., crosslinking reactions without the use of a solvent. This option is particularly useful in view of a processing of the materials according to the invention in injection moulding, because the thermoplastic starting materials are shaped in this process, whereupon the crosslinking into the desired shape follows.
The following examples illustrate the invention under consideration.
Abbreviated designations of the oligomers and the polymer networks
Cooligomers of the rac-dilactide
E Ethylene glycol
P Pentaerythrite
T 1,1,1-Tris(hydroxymethyl)ethane
C ε-hydroxycaproate
D β-hydroxyethoxy acetate
G Glycolate
F-PPG-Z
D Diol
M Dimethacrylate
T Triol
T-PPG-Z-b-LG-Z
The designations for the prepolymers used with the prefix N apply.
An exception is given by the networks that are produced by polyaddition of mixtures of oligo(propylene glycol)triols, oligo[(rac-lactate)-co-glycolate] tetrols and TMDI. In this case, the following abbreviated designations apply:
N-T-PPG(μPPG)-Z-LG
The networks N-EA, N-BA and N-HEA form additional exceptions. These are networks that are obtained by means of photochemically initiated polymerization of ethyl acrylate, butyl acrylate or (2-hydroxyethyl)acrylate. A volume of 0.5% by volume of the oligo(propylene glycol)dimethacrylate M-PPG-560 and the photoinitiator 2,2′-dimethoxy-2-phenylacetophenone (10 mg/mL) is added to the acrylates.
N-LG-ipX-N-Y(μY)-Z
In the case of interpenetrating systems whose components Y are prepared in a non-cross-linked form, (pre-IPNs), the auxiliary N is dropped in front of this component.
The preparation of star-shaped prepolymers such as oligo[(rac-lactate)-co-glycolate]triol or -tetrol is done by means of ring-opening copolymerization of rac-dilactide and diglycolide in the melting of the monomers with hydroxyfunctional initiators, with the addition of the catalyst dibutyltin (IV) oxide (DBTO). This synthesis path had proven to be suitable in the literature on the production of linear and branched oligomers with defined molar mass and terminal group functionality (D. K. Han, J. A. Hubbell, Macromolecules 29, 5233 (1996); D. K. Han, J. A. Hubbell, Macromolecules 30, 6077 (1997); R. F. Storey, J. S. Wiggins, A. D. Puckett, J. Polym. Sci.: Part A: Polym. Chem. 32, 2345 (1994); S. H. Kim. Y.-K. Han, Y. H. Kim, S. I. Hong, Makromol. Chem. 193, 1623 (1992)). Ethylene glycol, 1,1,1-tris(hydroxy-methyl)ethane or pentaerythrite are used as initiators of the ring-opening polymerization.
Oligo(lactate-co-hydroxycaproate) tetrols and oligo(lactate-hydroxyethoxy acetate) tetrols, as well as [oligo(propylene glycol)-block-oligo(rac-lactate)-co-glycolate)] triols are produced in a similar fashion.
a)Explanation of the abbreviations: see above.
b)The molar proportion of glycolate units χG is calculated using the1H-NMR spectra and converted into proportions by mass μG. The determination of the composition of the oligomers and the calculation of Mn according to 1H-NMR are described in Chap. 12.2.1.
c)n.d.: not determined
a)See above.
b)The molar proportion of β-hydroxyethoxy acetate units χD is calculated by evaluating the 1H-NMR spectra and converted into proportions by mass μD. The determination of the composition of the oligomers and the calculation of Mn according to 1H-NMR.
c)n.d.: not determined.
a)See above.
b)The determination of μPPG, DP and Mn (1H-NMR) is done using1H-NMR spectroscopy.
c)Mn of the macroinitiators according to the manufacturer's information is the basis for the values nI and MI.
The network synthesis takes place by means of polyaddition of the star-shaped macrotriols and tetrols with an aliphatic diisocyanate as a bifunctional coupling reagent (Type 1). Work is done here in solutions in dichloromethane. In standard experiments, an isomer mixture of 2,2,4 and 2,4,4 trimethylhexane-1,6-diisocyanate (TMDI), for example, is used as the diisocyanate. The intended purpose of the use of the isomer mixture is to prevent possible crystallization of diurethane segments. Also suitable are other diisocyanates.
Alternatively, mixtures of different prepolymers can be reacted with a diisocyanate, e.g., oligo(rac-lactate)-co(glycolate) tetrol with oligo(propylene glycol)triol and TMDI (Type II).
A different synthesis strategy is applied in the case of networks of Type III. In this case, a mixture of a tetrol, an oligo(propylene glycol)dimethacrylate and TMDI is produced. First the tetrol and the TMDI react together into a first network (pre-IPN). Subsequently, the radical cross-linking of the dimethacrylate is initiated by means of UV radiation, by means of which a second network is created (sequential IPN). As a result of the use of pre-IPNs, the permanent shape of the shape memory materials can be relatively easily and quickly adjusted to special requirements and geometries by means of UV radiation (FIG. F).
Another synthesis strategy consists of swelling a polyurethane network of Type I in an acrylate, and subsequently triggering a radical polymerization using UV light. Suitable are ethyl, butyl, hexyl or (2-hydroxyethyl)acrylate. In this way, one obtains an IPN of Type IV. Regardless of the acrylate used, two glass transitions are usually observed. When 2-(hydroxyethyl)acrylate is used, it is possible to adjust the hydrophilicity of the material (FIG. G). The bandwidth of medical applications of the prepared materials is expanded because of this possibility.
a) Isomer mixture of 2,2,4 and 2,4,4-trimethylhexane-1,6-diisocyanate;
b) cis/trans mixture of the isophorone diisocyanate,
c) cis/trans mixture of the 4,4′-methylene-bis(cyclohexyl isocyanate),
d) n.d.: not determined. Networks of P-LG(17)-1000 are destroyed during the swelling in chloroform, so that determination of G and Q are only possible with restrictions.
100c)
a) See above.
b) The solubility parameter δP is only insubstantially influenced by the β-hydroxyethoxy acetate content. For PPDO, a value of 19.0 MPa0.5, which corresponds to the value for PDLLA, is determined according to the group contribution method with molar attraction constants according to Small. All calculations therefore take place with a value for the interaction parameter x of 0.34. The density of the amorphous networks ρp is always set equal to 1.215 g · cm−3.
c) The determination of G is done by means of extraction with a mixture of diethyl ether and chloroform in a proportion by volume of roughly 1:1.
d) n.d.: not determined. Networks are destroyed during the swelling process in chloroform.
a) See above.
b) n.d.: not determined, is destroyed during swelling in chloroform.
a) See above.
b) Determined by means of1H-NMR spectroscopic examinations after reaction of the contained networks with deuterated trifluoroacetic acid.
c) n.d.: not determined.
a) See above.
b) IPNs break during the swelling.
a) See above.
a)See above.
b)A second glass transition is not detected.
a)See above.
b)The samples break when the value of εm is 100%.
The examples according to the invention demonstrate that the networks of the invention are shape memory materials that can be selectively produced, wherein good control of the network properties is possible. Preferred networks are amorphous and biodegradable and/or phase-segregated.
| Number | Date | Country | Kind |
|---|---|---|---|
| 103 40 392.2 | Sep 2003 | DE | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2004/009180 | 8/16/2004 | WO | 00 | 9/8/2008 |
