Patent Application
20100062036
The invention is directed to a multiblock copolymer with shape memory properties and a synthetic precursor of the multiblock copolymer.
Shape memory materials are those that can change their outward shape under the influence of an external stimulus. The present invention is concerned with thermosensitive shape memory plastics, also known as shape memory polymers. The shape memory effect is not a specific material characteristic of polymers; rather, it is a direct result of the combination of polymer structure and polymer morphology and techniques of processing and programming.
In elastomers, a shape memory functionality is achieved when the elastomer is stabilized in its deformed state within a particular temperature range. This can be achieved, for example, by using chain segments as molecular switches. One possibility for a switch function is a thermal transition (TTrans) in the chain segment within the temperature range of interest for the application. If the temperature is greater than TTrans of the switching segment, the segments are flexible and the polymer can be elastically deformed. The temporary shape is fixed by cooling below TTrans. When the polymer is heated again, the permanent shape is restored.
The field of biomedicine is an important area of application for shape memory polymers. In the last 30 years, synthetic, degradable implant materials have ushered in decisive advantages in a wide variety of therapies. Degradable implant materials include, for example, polyhydroxy acids such as polyglycolide or the copolyesters of L-lactic acid and glycolic acid. The appeal of degradable shape memory polymers could also be increased through their use as degradable implant materials; they offer a great potential for application in minimally invasive medicine. Degradable implants could be introduced into the body, for example, in a compressed (temporary) shape through a small incision and could adopt their stored, application-relevant shape when heated to body temperature. After a given time, the implant disintegrates; there is no need for a second operation for removal of the implant.
It is precisely in an application of this kind that the risk of a toxic effect of the shape memory material and its degradation products is significant; these degradation products should be biocompatible.
In this connection, poly(ε-caprolactone)diols with melting temperatures between 46° C. and 64° C. and amorphous copolyesters of diglycolides with glass transition temperatures in the range of 35° C. to 50° C. are described as suitable switching segments for degradable shape memory polymers. The known switching segments have an average molecular weight MW between 500 and 10,000 and a thermal transition of the switching segments in the range between room temperature and body temperature which is favorable for biomedical applications.
A biocompatible and, at the same time, biodegradable multiblock copolymer with shape memory properties can be obtained from crystallizable hard segments of poly(p-dioxanone) and an amorphous switching segment such as a crystallizable poly(ε-caprolactone) segment. The thermoplastic elastomers are produced by means of the co-condensation of two different macrodiols with a difunctional crosslinking unit (for example, diisocyanate, diacid dichloride, or phosgene). To obtain the desired mechanical characteristics, it is very important to achieve high molecular weights MW in the range of 100,000 g/mol. Molecular parameters of this polymer system are the molecular weight, microstructure (sequence), comonomer ratio of the macrodiols, and the hard segment proportion in the multiblock copolymer.
In spite of the above-described advances in the field, there is still a substantial need for shape memory polymers which are hydrolytically degradable in the body, whose degradation products are safe in toxicological respects, and which further have advantageous properties for the planned purpose such as, for example, switching temperatures in the range from 30° C. to 60° C. and processing temperatures of up to 200° C. in biomedical applications.
Therefore, it is the object of the present invention to provide novel biodegradable shape memory materials which have improved or at least equivalent properties in comparison to the known materials.
According to a first aspect of the invention, the above-stated object is met by the multiblock copolymer with shape memory properties according to claim 1. The multiblock copolymer according to the invention contains:
The linear multiblock copolymer according to the invention is distinguished by the presence of a poly(depsipeptide) segment that is hydrolytically degradable, and in that the degradation products, namely, amino acids and hydroxy acids, are well-tolerated biologically. The amino acids occurring by hydrolytic degradation are capable of acting as acid/base buffers and accordingly buffer the acidity of the hydroxy acids occurring in the hydrolytic degradation. This mechanism could present a possibility for favorably influencing the course of the healing of wounds, because the release of acid degradation products generally intensifies the occurring inflammation processes. Also, the formation of cationic surface charges in polymers with poly(depsipeptide) blocks during the hydrolytic degradation could be used specifically to moderate the wound healing process. The poly(depsipeptide) segment can act as a hard segment and/or switching segment in the multiblock copolymer. When used as a switching segment, the glass transition temperature (usually in the temperature range between 40° C. and 60° C.) of the amorphous component of the phase determined by the poly(depsipeptide) segment is used as switching temperature. The combination of poly(depsipeptide) segments and poly(ε-caprolactone) segments in multiblock copolymers delivers a hydrolytically degradable thermoplastic elastomer with shape memory properties and switching temperatures in the range of 30° C. to 90° C. and processing temperatures of up to 200° C. in case of blocks which form hard segments and which are based on leucine and diglycolide. Hard segments and switching segments are both formed so as to be hydrolytically degradable.
The indicated molecular weights are to be determined by gel permeation chromatography (GPC). The determination can be carried out in a supplementary manner based on the 1H NMR spectrum.
A poly(depsipeptide) segment of the following formula (1) is preferred:
where X is a bridge selected from the group:
where o=2-20 and p=1-10;
Further, X preferably represents
where o=8; or represents
where p=1. Poly(depsipeptide) segments with the variants of the central bridge element (starter) mentioned above can easily be synthesized and, based on first trials, have favorable material characteristics for application in the field of medical engineering.
Further, it is preferable when R in formula (1) represents H, methyl, 1-methylethyl, 2-methylpropyl, or 1-methylpropyl. Accordingly, on the one hand, synthesis rules, known per se, for ring-opening polymerization of morpholine-2,5-dione derivatives with a corresponding bridge-building diol as starter can be drawn upon in the production of the poly(depsipeptide) segments. On the other hand, the generated monomer units in the poly(depsipeptide) segment correspond to the natural amino acids glycine, alanine, valine, leucine and isoleucine, so that a high biocompatibility of the polymer and its degradation products can be expected.
Further—particularly also in combination with each of the above-mentioned variations in the poly(depsipeptide) segment—the poly(ε-caprolactone) segment of formula (2) is preferably:
wherein Y represents
where s=1-10; and
The poly(depsipeptide) segments and poly(ε-caprolactone) segments in the multiblock copolymer are preferably coupled by bridges of formulas (3a) and/or (3b):
Further, it is preferable when a weight ratio of the poly(depsipeptide) segments to the poly(ε-caprolactone) segments is in the range of 1:1 to 1:10.
Finally, it is preferable when an average molecular weight MW of the multiblock copolymer is in the range of 10,000 to 100,000 g/mol.
A second aspect of the invention is directed to the poly(depsipeptide) of formula (4) which occurs as an intermediate product of the synthesis:
wherein X is a bridge selected from the group:
where o=2-20 and p=1-10;
A third aspect of the invention consists in the use of the multiblock copolymer according to the invention of the type described above as an implant material, as a polymer matrix for the controlled release of active ingredients (active ingredient depots and coatings for encapsulating active ingredients) and as a material for producing framework structures and leading structures (polymer scaffolds and alloplastic scaffolds) for tissue engineering.
The invention will be described more fully in the following with reference to embodiment examples and accompanying drawings.
Poly(depsipeptides) are alternating copolymers of α-amino acids and α-hydroxy acids. Different combinations of α-amino acids (for example, L-leucine, L-valine, glycine, L-lysine or L-glutamic acid) and an α-hydroxy acid (glycolic acid, L,L-dilactide or rac-dilactide) can be converted into new materials of a nontoxic and biodegradable nature. A known synthetic approach to poly(depsipeptides) is ring-opening polymerization of morpholine-2,5-dione derivatives in the presence of tin dioctanoate (Sn(oct)2) as catalyst. Further, an enzymatically catalyzed ring-opening polymerization of morpholine-2,5-diones has been reported. Further, block copolymers of 3(S)-isopropyl-morpholine-2,5-dione and polyethylene oxide (PEO) which are accessible through ring-opening polymerization are known.
Poly(α-hydroxyalkonates) such as poly(L-lactides) or copolymers of L,L-dilactides and diglycolides are used as resorbable implant materials, biodegradable suture material and matrixes for a controlled release of active ingredients. Poly(ε-caprolactone) blocks and poly(p-dioxanone) blocks forming thermoplastic multiblock copolymers with semicrystalline phases and AB polymer networks based on semicrystalline poly(ε-caprolactone) chain segments have been described as biodegradable memory polymers (A. Lendlein et al., Proc. Natl. Acad. Sci. USA 2001, 98(3), 842; A. Lendlein et al., Science 2002, 296(5573), 1673). Biodegradable amorphous poly[(rac-lactide(-ran-glycolide]-urethane networks with shape memory properties have been synthesized by coupling with star-shaped oligomers using an isomeric mixture of 2,2,4- and 2,4,4-trimethyl hexamethylene diisocyanate (TMDI) (A. Lendlein et al. Angew. Chem. 2005, 117, 1212).
The polymerization was carried out in a dry glass flask with a stirrer. The flask was heated to 50° C., evacuated, and rinsed with dry nitrogen. The flask was charged with 31.3 g of 3(S)-isobutylmorpholine-2,5-dione (IBMD), 0.349 mL of ethylene glycol, and 4 ml of a 0.3-molar Sn(oct)2 solution. The flask was then evacuated and rinsed repeatedly with dry nitrogen. The reaction mixture was left under nitrogen and heated to 140° C. in an oil bath. After 24 hours, the flask was removed from the oil bath and cooled to room temperature. The product was dissolved in 100 mL DMF and precipitated in 1L diethyl ether. The obtained polymer was collected and dried under vacuum at room temperature for 24 hours. Yield: 80%.
1H NMR (300 MHz, DMSO): δ=0.80-0.90 ppm (2 d, 6H, CH3 8 and 9), 1.45-1.80 ppm (m, 3H, CH 7 and CH2 6), 4.20-4.30 ppm (CH2 2 in the end group), 4.30-4.50 ppm (CH 5), 4.50-4.73 ppm (AB system, ABJ=14.6 Hz, 2H, CH2, 2, isot.), 5.49-5.55 ppm (t, 3J=5.8 Hz 1H, OH 1), 8.30-8.40 ppm (d, 3J=7.7 Hz 1H, NH 4); starter: δ=3.80-3.90 ppm (d, 3J=5.7 Hz, 4H, CH2 11 and 12).
13C NMR (75.41 MHz, DMSO): δ=21.1 ppm (CH3 8 or 9), 22.8 ppm (CH3 8 or 9), 24.1 ppm (CH 7), 40.4 ppm (CH2 6), 49.9 ppm (CH 5), 62.1 (CH2 2), 166.6 ppm (COO 10), 171.7 ppm (CONH 3, syndiot.), 171.8 ppm (CONH 3, isot.), 172.3 (CONH 3 end group); starter: δ=61.2 ppm (CH2 11 and 12).
Mn=6,300 g/mol (1H NMR), 5,700 g/mol (determination of OH number).
Production is carried out by a method analogous to that for producing PIBMD, but with the starting materials 3(S)-sec-butylmorpholine-2,5-dione and 1,8-octanediol.
1H NMR (300 MHz, CDCl3): δ=0.90-1.09 ppm (2 d, 6H, CH3 8 and 9), 1.21-1.75 ppm (m, 2H, CH2 7), 1.96-2.04 ppm (m, 1H, CH 6), 4.10-4.20 ppm (CH2 2 end group), 4.24-4.30 ppm (m, 1H, CH 5), 4.43-4.90 ppm (AB system, ABJ=14.6 Hz, 2H, CH2, 2, isot.), 7.50-7.70 ppm (1H, NH 4); starter: δ=4.05-4.10 ppm (4H, CH2 11 and 12).
Production is carried out by a method analogous to that for producing PIBMD, but with the starter materials 3-methylmorpholine-2,5-dione and 1,8-octanediol.
1H NMR (300 MHz, DMSO): δ=1.2-1.4 ppm (d, 3H, CH3 6), 4.3-4.4 ppm (m, 1H, CH 5), 4.5-4.7 ppm (m, 2H, CH2 2), 8.3-8.5 ppm (2 d, 1H, NH 4); starter: δ=3.8-3.9 ppm (m, 4H, CH2 11 and 12).
Table 1 shows selected properties of the PIBMD, PBMD and PMMD polymers.
1)Molecular weight by determination of the OH number.
2)Molecular weight based on 1H NMR spectrum.
3)Molecular weight GPC.
4)Molecular weight distribution GPC.
5)Differential scanning calorimetry (DSC).
A mixture of 24.0 g (12 mmol) of PCL (poly(ε-caprolactone); trade name CAPA2304 by Solvay Caprolactones, UK; average molecular weight MW 3000 g/mol, 22.5 g (4 mmol) of PIBMD, 16 mmol of TMDI, 43 μL of dibutyl tin laurate (approximately 0.1 percent by weight) and 110 g of N-methylpyrrolidone were added to a two-neck round bottom flask under nitrogen accompanied by continuous stirring by means of a magnetic stirrer. Heating was carried out to a temperature of 80° C. and, after 24 hours, the reaction mixture was analyzed by IR spectroscopy and gel permeation chromatography (GPC). After the NCO bands disappeared in IR at 2270 cm−1, 100 μL of TMDI were added and stirring was carried out for another 24 hours. Subsequently, the reaction mixture was precipitated with 200 mL of 1,2-dichloroethane and with a tenfold excess of diethyl ether. The precipitated multiblock copolymer was collected by filtration and dried under vacuum at room temperature for 24 hours. Yield: 90%.
1H NMR (300 MHz, DMSO): PIBMD block: δ=0.80-0.90 ppm (2 d, 6H, CH3 8 and 9), 1.45-1.80 ppm (m, 3H, CH and CH2), 4.30-4.50 ppm (CH), 4.50-4.73 ppm (AB system, ABJ=14.6 Hz, 2H, CH2, isot.), 8.30-8.40 ppm (d, 3J=7.7 Hz 1H, NH); starter: δ=3.82-3.90 ppm (d, 3J=5.7 Hz, 4H, CH2); PCL block: δ=1.23-1.37 ppm (m, 2H, CH2), 1.46-1.71 ppm (m, 4H, CH2, overlapping with PIBMD block), 2.23-2.30 ppm (t, 3J=7.3 Hz 2H, CH2), 3.94-4.01 ppm (t, 3J=6.6 Hz 2H, CH2); starter: δ=3.57-3.62 ppm (m, 4H, CH2) and 4.08-4.13 ppm (m, CH2); TMDI: δ=0.76-0.93 ppm (m, CH3, overlapping with PIBMD block), 1.05-1.19 ppm (m, CH2 and CH), 2.68-3.02 ppm (m, CH2).
Production was carried out by a method analogous to that used for the production of PCL/PIBMD.
1H NMR (300 MHz, CDCl3): PMMD block: δ=1.3-1.4 ppm (CH3), 4.3-4.4 ppm (s, CH), 4.5-4.7 ppm (CH2), 7.6-8.0 ppm (NH); starter: δ=3.6 ppm (CH2). PCL block: δ=1.4-1.5 ppm (m, CH2 overlapping with PMMD block), 1.5-1.7 ppm (m, CH2), 2.2-2.40 ppm (2H, CH2), 4.0-4.1 ppm (2H, CH2); starter: δ=3.6-3.7 ppm (m, 4H, CH2) and 4.2 ppm (m, CH2). TMDI: δ=0.80-0.90 ppm (m, CH3), 0.9-1.0 ppm (m, CH2 and CH), 2.8-3.2 ppm (m, CH2).
Table 2 shows selected properties of the PCL/PIBMD and PCL/PMMD multiblock copolymers.
1)Molecular weight GPC.
2)Molecular weight distribution GPC.
3)First peak in DSC chart.
4)Enthalpy of the first peak in the DSC chart.
5)Second peak in the DSC chart.
6)Enthalpy of the second peak in the DSC chart.
7)Glass transition temperature from DSC, first run.
8)Glass transition temperature from DSC, second run.
A film with a thickness of 400 μm was produced from the multiblock copolymer PCL/PIBMD by compression melting at 180° C. and 90 bar. The DSC of the PCL/PIBMD film shows that the enthalpy of the PIBMD blocks was very low. The PIBMD blocks must have a high crystallinity to fix the permanent shape of the film. In order to increase the crystallinity of the PIBMD blocks, the film was tempered at 100° C. for 30 minutes and at 80° C. for 24 hours and was then gradually cooled to room temperature.
The PCL/PIBMD multiblock copolymer built from poly(ε-caprolactone) blocks (PCL blocks) and PIBMD blocks was synthesized using 2,2,4- and 2,4,4-trimethyl hexamethylene diisocyanate (TMDI) as coupling reagent.
The phase determined by the PCL blocks with a melting temperature of about 37° C. functions as a switching segment, while the crystalline phase with the higher melting temperature determined by the PIBMD blocks represents the hard segment. The topography and the phase behavior of the multiblock copolymer were analyzed using scanning force microscopy (AFM) based on a polymer film applied to a silicone substrate. The surface topographies of the samples were examined at room temperature to detect the surface morphology above the PCL melting temperature. Subsequently, the samples were cooled again to room temperature.
The PCL domains had an expansion of up to 400 nm, whereas PIBMD blocks were present in continuous phase. The comparison of the topography and the phase view shows that the phase domain does not influence the topography of the film. After cooling to room temperature, the PCL phase recrystallized and the AFM photograph resembled the photographs prior to heating. Accordingly, the PCL/PIBMD multiblock copolymer shows a microphase separation between the PCL phase and the PIBMD phase, which leads to the formation of a kind of nano-composite between the PCL blocks determining the switching segment and the PIBMD blocks determining the hard segment.
A thermal analysis by means of DSC measurement of the multiblock copolymers confirmed that these multiblock copolymers are semicrystalline. PCL diol 3K had a double melting point at 48° C. and 50° C. (ΔH=60.5 J/g) and a glass transition at about −60° C. PIBMD 5K had a melting temperature of about 170° C. (ΔH=20.3 J/g) and a glass transition at 43° C. The two melting temperatures in the multiblock copolymer were 170° C. and 34° C. for the PIBMD blocks and PCL blocks, respectively. The crystalline PIBMD phase prevents a crystallization of the PCL blocks. In the second heating process, PIBMD recrystallized at about 101° C. and showed a melt transition at 170° C. (39.4 J/g), while the PCL phase had a melting temperature of 37° C. (3.0 J/g).
The mechanical properties of the PCL/PIBMD multiblock copolymers were analyzed by means of tensile/elongation tests above and below Tm of the PCL blocks. The results of these tests are compiled in Table 3.
f,2-5
r,2-5
1)Determined at 25° C.
2)Determined at 75° C.
A PCL/PIBMD multiblock copolymer in its permanent shape as a helically twisted strip was changed from its permanent shape at high temperature (T=120° C.) into the temporary shape (flat polymer strip). The deformed shape was fixed by cooling to room temperature. In order to restore the permanent shape, the sample was heated above the switching temperature TTrans (to about 60° C.) and the original permanent shape was restored. The macroscopic shape memory effect of PCL-PIBMD is shown in
The shape memory properties of the PCL-PIBMD multiblock copolymer were quantified by means of cyclical thermomechanical examinations, wherein a maximum elongation of εm=50% was applied. The measurement results of five successive thermocycles are shown in
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2006 023 365.4 | May 2006 | DE | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2007/054328 | 5/4/2007 | WO | 00 | 5/14/2009 |
