Triblock copolymers, their preparation and use

Abstract

The present invention relates to a triblock copolymer comprising the structure "polylactic acid (PLA)-X-polylactic acid (PLA)", where X is an unsaturated polymacrolactone (PML) or a copolymer comprising PML and a polyester. The present invention further relates to a method for obtaining said triblock copolymer and its use.

Description

[Technical field]

[0001] The present invention relates to the field of polymer technology. In particular, the present invention relates to triblock copolymers, particularly triblock copolymers having a functionalized polymacrolactone (PML) in the midblock and polylactic acid in the outer blocks, their preparation methods and their uses. [Background technology]

[0002] Polylactic acid (PLA), a bio-based, biocompatible and biodegradable polyester, is a promising polymer with excellent properties for various applications, such as packaging, agriculture or medicine. However, it also has some drawbacks that must be improved in order to have a real impact in these fields. First, PLA does not have functional groups, which considerably limits its applications, especially in advanced fields such as biomedicine and electronics. For example, functional groups are used to bind bioactive molecules or drugs and to be used as drug delivery systems. Another example is the incorporation of hydrophilic molecules that increase the biodegradation rate. Thus, adding functional sites can significantly improve the performance of PLA and expand its range of applications. Second, when it comes to mechanical properties, PLA is a hard and brittle material. That is, it can withstand moderate forces but deforms very little (less than 10%) before breaking. Although these are excellent properties, some applications require the material to undergo plastic deformation or exhibit flexible behavior before breaking. For example, the design of temporary biomedical implants requires tough and deformable materials rather than brittle materials that can disintegrate into small pieces in the body.

[0003] Therefore, providing functional moieties and improving the mechanical properties have become essential challenges in the research and development of advanced PLA. Indeed, several solutions have been proposed in the literature to modify the properties of PLA.

[0004] Several strategies have been proposed to provide new functional groups to PLA. In general, these strategies are based on the use of functional comonomers as initiators or on the reaction of functional molecules with the PLA end chain groups. The former approach requires the use of functional monomers or initiators with the desired properties, as previously mentioned. For example, PEG has been used as an initiator for lactide polymerization to obtain hydrophilic scaffolds of PLA with improved degradation rates (Zhu, X.; Zhong, T.; Huang, R.; Wan, A. Preparation of Hydrophilic Poly(Lactic Acid) Tissue Engineering Scaffold via (PLA)-(PLA-b-PEG)-(PEG) Solution Casting and Thermal-Induced Surface Structural Transformation. J. Biomater. Sci. Polym. Ed. 2015, 26, 1286-1296.). Other strategies include the grafting of hydrophilic or bioactive molecules onto PLA, often grafted to the surface via the end chain groups.For example, PLA has been grafted with amine-terminated structures (anorkar, AV; Fritz, EW; Burg, KJL; Metters, AT; Hirt, DE Grafting Amine-Terminated Branched Architectures from Poly(L-Lactide) Film Surfaces for Improved Cell Attachment. J. Biomed. Mater. Res. - Part B Appl. Biomater. 2007, 81, 142-152.) or osteoinductive growth factors (Edlund, U.; Danmark, S.; Albertsson, AC A Strategy for the Covalent Functionalization of Resorbable Polymers with Heparin and Osteoinductive Growth Factor. Biomacromolecules 2008, 9, 901-905.) to improve hydrophilicity and biomedical performance.

[0005] Similarly, the modification of the mechanical properties of PLA has already been addressed. A well-known strategy is the synthesis of thermoplastic elastomers (TPEs), which typically have a triblock structure. This solution combines the rubber-like behavior of soft polymers, the mechanical strength of hard segments, and the easy processability of thermoplastics, thanks to physical crosslinks induced by separated block microphases. There are several examples in the literature of PLA copolymerized with softer, more flexible polyesters. Examples include polybutylene succinate (PBS) (Jia, L.; Yin, L.; Li, Y.; Li, Q.; Yang, J.; Yu, J.; Shi, T.; Fang, Q.; Cao, A. New Enantiomeric Polylactide-Block-Poly(Butylene Succinate)-Block- Polylactides: Syntheses, Characterization and in Situ Self-Assembly. Macromol. Biosci. 2005, 5, 526-538.), polybutylene adipate terephthalate (PBAT) (Ding, Y.; Lu, B.; Wang, P.; Wang, G.; Ji, J. PLA-PBAT-PLA Tri-Block Copolymers: Effective Compatibilizers for Promotion of the Mechanical and Rheological Properties of PLA / PBAT Blends. Polym. Degrad. Stab. 2018, 147, 41-48.), lactones, e.g., poly(ε-caprolactone) (PCL) (Maglio, G.; Migliozzi, A.; Palumbo, R. Thermal Properties of Di- and Triblock Copolymers of Poly(l-Lactide) with Poly(Oxyethylene) or Poly(ε-Caprolactone). Polymer (Guildf). 2002, 44, 369-375.), poly(δ-valerolactone) (Jing, Z.; Shi, X.; Zhang, G. Synthesis and Properties of Biodegradable Supramolecular Polymers Based on Polylactide- Block-Poly(δ-Valerolactone)-Block-Polylactide Triblock Copolymers. Polym. Int. 2017, 66, 1487-1497.) or poly(ε-decalactone) (Olsen, P.; Borke, T.; Odelius, K.; Albertsson, A.-C. ε-Decalactone: A Thermoresilient and Toughening Comonomer to Poly(l-Lactide). Biomacromolecules 2013, 14, 2883-2890.). However, many of these solutions contain highly crystalline polymers with long saturated backbones, which can make the polymers difficult to biodegrade. Furthermore, neither PLA nor these copolymers have more than two functional groups in the end chains. This is a major limitation if further modifications are required. For example, depending on the end application, it may be necessary to increase the degradation rate or add new functional molecules (biological activity, electrical conductivity, barrier properties, etc.). Summary of the Invention [Problem to be solved by the invention]

[0006] In view of the above, the problem that the present invention aims to solve is to provide biobased and biocompatible synthetic polymers in the form of triblock copolymers with multiple functionalization sites, which allow the preparation of polymers with tunable biodegradation behavior and mechanical properties. The extensive functionalization may allow the polymers to be applied in many fields such as biomedical, packaging, electronics, agriculture, etc. [Means for solving the problem]

[0007] The present inventors have surprisingly discovered a triblock copolymer that overcomes the previous drawbacks. The triblock copolymer has an ABA structure with a biobased and biodegradable segment A (PLLA or PDLLA) and a biobased and biodegradable unsaturated soft segment B (PML). Surprisingly, the synergistic effect of combining the functionalization of PLA and the synthesis of TPEs with tunable mechanical properties in a single strategy was achieved by using the unsaturated PML as a macroinitiator in lactide ring-opening polymerization (ROP). Moreover, the synthetic route and manufacturing method for obtaining the triblock copolymer of the present invention are cost-effective and easily transferable to industrial scale.

[0008] In a first aspect, the present invention provides a compound having the following structure (I): Polylactic acid (PLA)-X-Polylactic acid (PLA) (I) [In the formula, X is an unsaturated polymacrolactone (PML) or a copolymer comprising PML and a polyester. The present invention relates to a triblock copolymer comprising or consisting of:

[0009] In a second aspect, the present invention relates to a method for obtaining a triblock copolymer according to the first aspect of the invention.

[0010] In a third aspect, the present invention relates to the use of a triblock copolymer according to the first aspect of the invention. [Brief description of the drawings]

[0011] [Figure 1] Figure 1 shows the reaction scheme of PML obtained by bulk e-ROP of Globaride and 6-ω-hexadecene lactone. [Diagram 2] FIG. 2 shows the reaction scheme for the synthesis of PLA-PML-PLA triblock copolymers by bulk ROP using PML as a macroinitiator. [Diagram 3]FIG. 3 shows the H NMR spectrum and peak assignments of the PLLA174-PGL63-PLLA174 triblock copolymer. [Figure 4] FIG. 4 shows the 13C NMR spectrum of the PLLA174-PGL63-PLLA174 triblock copolymer with details of the carbonyl region. [Diagram 5] FIG. 5 shows the stress-strain curves of PLLA (dark line) and PDLLA104-PGL106-PLLA104 (light line) under tensile loading. [Figure 6] FIG. 6 shows the DSC cooling (a) and heating (b) traces of PLLA, PGL and the triblock copolymer at 10° C. / min. [Figure 7] FIG. 7 shows a comparison of 1H NMR spectra of PDLLA139-PGL85-PDLLA139 before (light line) and after (dark line) functionalization with COOH-PEG24-COOH. [Figure 8] FIG. 8 shows the evolution of a static water droplet on the roughened surface of porous PDLLA139-PGL85-PDLLA139 and COOH-PEG24-PDLLA139-PGL85-PDLLA139-PEG24-COOH scaffolds. [Figure 9] FIG. 9 shows the stress-strain curves of PDLLA139-PGL85-PDLLA139 (light line) and COOH-PEG24-PDLLA139-PGL85-PDLLA139-PEG24-COOH (dark line) under tensile loading. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] In a first aspect, the present invention provides a compound having the following structure (I): Polylactic acid (PLA)-X-Polylactic acid (PLA) (I) [In the formula, X is an unsaturated polymacrolactone (PML) or a copolymer comprising PML and a polyester. The present invention relates to a triblock copolymer comprising:

[0013] In certain embodiments, the present invention provides a compound having the following structure (I): Polylactic acid (PLA)-X-Polylactic acid (PLA) (I) [In the formula, X is an unsaturated polymacrolactone (PML) or a copolymer comprising PML and a polyester. The present invention relates to a triblock copolymer consisting of

[0014] In this disclosure and claims, terms such as "comprises," "comprising," "containing," and "having" are open-ended terms and can mean "includes," "including," etc., while terms such as "consisting of" or "consists of" refer to the elements recited after those terms and to the exclusion of other terms not recited.

[0015] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The singular terms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. For example, "an unsaturated polymacrolactone" or "the PML" includes the option of one unsaturated polymacrolactone and the option of two or more identical or different unsaturated polymacrolactones. Similarly, "a copolymer" includes the option of one copolymer and the option of two or more identical or different copolymers, which include one or more identical or different PMLs and one or more identical or different polyesters. Thus, in structure (I), there is the option of having a combination of different PML molecules acting as PMLs and a combination of different polyester molecules acting as polyesters. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0016] In a preferred embodiment of the first aspect, the PML is selected from polyglobarid (PGL), poly(ambrettolide) (PAmb), poly(6-ω-hexadecene lactone) (P6HDL), and combinations thereof. In another preferred embodiment of the second aspect, the PML is any combination of polyglobarid (PGL), poly(ambrettolide) (PAmb) and poly(6-ω-hexadecene lactone) (P6HDL).

[0017] In another preferred embodiment of the first aspect, the polyester is selected from polypentadecalactone (PPDL), polycaprolactone (PCL), polyglycolic acid (PGA) and poly(paradioxanone). In another preferred embodiment of the first aspect, the polyester is any combination of polypentadecalactone (PPDL), polycaprolactone (PCL), polyglycolic acid (PGA) and poly(paradioxanone).

[0018] In another preferred embodiment, "X" in structure (I) is a copolymer of PML and a polyester.

[0019] In another preferred embodiment of the first aspect, the triblock copolymer is end-functionalized or grafted through the PML double bonds with molecules containing hydroxyl (-OH), carboxyl (-COOH), or amine (-NH2) moieties.

[0020] In another preferred embodiment of the first aspect, the triblock copolymer is crosslinked by self-crosslinking reactions of the PML double bonds or by crosslinking reactions of the PML double bonds with other crosslinking molecules, such as thiols, amines, maleimides, vinyl sulfones or acrylates.

[0021] In a second aspect, the present invention relates to a compound as defined by the first aspect, namely, a compound having the following structure (I): Polylactic acid (PLA)-X-Polylactic acid (PLA) (I) [In the formula, X is an unsaturated polymacrolactone (PML) or a copolymer comprising PML and a polyester. The present invention relates to a process for obtaining a triblock copolymer having the following steps: (a) preparing an unsaturated polymacrolactone (PML) by ring-opening polymerization (ROP) of the corresponding unsaturated macrolactone (ML) using a diol as an initiator; Here, when X is a copolymer containing PML and a polyester, after step (a) and before the next step (c), the following step is carried out: (bi) when the polyester is derived from a cyclic ester monomer, preparing a copolymer comprising PML and a polyester by ring-opening polymerization (ROP) of the cyclic ester monomer using the unsaturated PML obtained in step (a) as a macroinitiator; or (b-ii) when the polyester is derived from an acyclic ester monomer, preparing a copolymer comprising PML and a polyester by polycondensation of the acyclic ester monomer using the unsaturated PML obtained in step (a) as a comonomer; and there is an additional step (b) consisting of (c) polymerizing lactide by ring-opening polymerization (ROP) using the unsaturated polymacrolactone obtained in step (a) or the copolymer obtained in step (b) as a macroinitiator and tin(II) 2-ethylhexanoate as a catalyst. Includes.

[0022] In another embodiment, when X in formula (I) is a copolymer, the process for obtaining a triblock copolymer as defined by the first aspect, i.e. having the following structure (I), comprises the following steps: (1a) preparing a copolymer of PML and polyester by ring-opening polymerization (ROP) of the corresponding unsaturated macrolactone (ML) with a cyclic ester using a diol as an initiator; or (1b) preparing a copolymer of PML and a polyester by polycondensation of the corresponding ML with a diol and a dicarboxylic acid or derivative, if the comonomer is not a cyclic ester; (2) polymerizing lactide by ring-opening polymerization (ROP) using the unsaturated polymacrolactone obtained in step (1a) or (1b) as a macroinitiator and catalyzed by tin(II) 2-ethylhexanoate; Includes.

[0023] In a further embodiment, after the lactide polymerization step (i.e. step (c) or step (2) depending on the process embodiment), the following steps are performed: - reacting the hydroxyl (-OH) end groups of the triblock copolymer with carboxyl (-COOH) or amine (-NH) groups by carbodiimide chemistry if the triblock copolymer is end-functionalized; or - if the triblock copolymer is grafted, reacting the double bonds of the PML blocks with thiol-containing molecules by thiol-ene "click" chemistry; or - if the triblock copolymer is crosslinked, reacting the double bonds of the PML blocks with each other or with other crosslinking molecules, such as thiols, amines, maleimides, vinylsulfones or acrylates. There are additional steps including:

[0024] In a preferred embodiment of the second aspect, the PML is selected from polyglobarid (PGL), poly(ambrettolide) (PAmb) and poly(6-ω-hexadecene lactone) (P6HDL). In another preferred embodiment of the second aspect, the PML is any combination of polyglobarid (PGL), poly(ambrettolide) (PAmb) and poly(6-ω-hexadecene lactone) (P6HDL).

[0025] In another preferred embodiment of the second aspect, the polyester is selected from polypentadecalactone (PPDL), polycaprolactone (PCL), polyglycolic acid (PGA) and poly(paradioxanone). In another preferred embodiment of the second aspect, the polyester is any combination of polypentadecalactone (PPDL), polycaprolactone (PCL), polyglycolic acid (PGA) and poly(paradioxanone).

[0026] In another preferred embodiment, the lactide used in step (c) or step (2) is L-lactide or a mixture of L-lactide and D-lactide.

[0027] In another preferred embodiment, step (a) or step (1a) or (1b) is carried out in bulk under an inert atmosphere.

[0028] In another preferred embodiment, step (a) or step (1a) or (1b) is carried out using a catalyst. In a further preferred embodiment, said catalyst is the Candida Antarctica Lipase B (CALB) enzyme.

[0029] In another preferred embodiment, step (bi) or (b-ii) is carried out in bulk under an inert atmosphere.

[0030] In another preferred embodiment, step (bi) or (b-ii) is carried out using a catalyst. In a further preferred embodiment, said catalyst is the Candida antarctica lipase B (CALB) enzyme.

[0031] In another preferred embodiment, step (c) or step (2) is carried out in bulk at 120 to 190° C. under an inert atmosphere.

[0032] In another preferred embodiment, the concentration of tin(II) 2-ethylhexanoate is 0.025 to 0.10% by weight.

[0033] In another preferred embodiment, the concentration of the macroinitiator PML or the copolymer of PML and polyester is 10 to 50 mol %.

[0034] In another preferred embodiment, at the end of each polymerization, unreacted monomers are removed and the catalyst is removed or deactivated. There are several ways to perform such removal or deactivation. In a further preferred embodiment, the removal is performed by dissolving the reaction mixture in a solvent (e.g., chloroform) and precipitating in cold methanol. However, when large amounts of reactants are used (e.g., 1 kg), the removal / deactivation can be performed under vacuum without the use of a solvent.

[0035] In a third aspect, the present invention relates to the use of a triblock copolymer as defined according to the first aspect of the invention in the preparation of a) medical devices for tissue regeneration, b) medical devices for drug delivery systems, c) lab-on-a-chip and organ-on-a-chip devices, d) hydrogels for health and smart agriculture applications, e) sensors, biosensors and electrodes, f) electronics, g) packaging films and trays, h) textiles and synthetic leather, i) coatings and surface protection solutions or j) additives for masterbatches or blend compatibilization.

[0036] Block copolymers, especially those with diblock and triblock structures, are frequently used as compatibilizers for immiscible polymer blends. The immiscibility of polymer blends is caused by high interfacial tension between the components, and poor interfacial adhesion leads to phase separation and inferior physicochemical properties compared to the separated components. Block copolymers play an important role in compatibilizing immiscible blends, since they can reduce the interfacial tension and improve the interfacial adhesion by placing themselves at the interface of the separated phases. Each block of the copolymer is rather concentrated in one of the separated phases and acts as a physical bond between them. As a result, the compatibilized blend has improved properties.

[0037] Furthermore, this functional triblock copolymer may be targeted in the biomedical field to create scaffolds for tissue regeneration and drug delivery systems. Controlling the length, composition, and molecular weight of each block allows for the creation of short-term or long-term medical devices. Furthermore, functionalization of the triblock copolymers with the end groups or double bonds of PML allows the addition of hydrophilic and non-fouling molecules such as PEG. The amphiphilic structure of these PEG-containing triblock copolymers facilitates drug encapsulation, and the non-fouling nature of PEG reduces the body's inflammatory response in implantable medical devices. Furthermore, the unsaturated nature of the PML block also allows for the covalent attachment of drugs and other bioactive molecules to the triblock copolymers.

[0038] Furthermore, PLA has been widely investigated as a bio-based solution for the packaging industry. However, neat PLA does not have properties that allow it to compete with current standard polymers such as PET and PE. Mechanical properties, barrier properties and transparency are the main limitations. The triblock copolymers proposed in this invention make it possible to obtain flexible materials with excellent barrier properties, while transparency can also be achieved by functionalization of the PML double bonds to reduce the crystallinity of the polymer.

[0039] As mentioned above, the proposed triblock copolymers not only have tunable mechanical and physical properties, but are also biocompatible. Thus, they offer a competitive advantage over other polymer substrates traditionally used in the electronics and textile industries. For example, by adjusting the block length ratio (A / B), the triblock copolymers of the present invention meet the flexibility requirements for use in electronic devices, which is an unsolved requirement for bio-based biocompatible polymers. This allows them to be used as substrates for consumer electronics or for sensor and biosensor development. Indeed, PLA has been shown to offer advanced properties in microfluidic devices such as organ chips (Ongaro, AE; Di Giuseppe, D.; Kermanizadeh, A.; Miguelez Crespo, A.; Mencattini, A.; Ghibelli, L.; Mancini, V.; Wlodarczyk, KL; Hand, DP; Martinelli, E.; et al. Polylactic Is a Sustainable, Low Absorption, Low Autofluorescence Alternative to Other Plastics for Microfluidic and Organ-on-Chip Applications. Anal. Chem. 2020, 92, 6693-6701.) and enhance the properties of PDMS.

[0040] The properties of the triblock copolymers of the present invention make them suitable for applications where fibers are needed, such as the textile field. Furthermore, the triblock copolymers of the present invention have multiple functionalization sites, making it possible to provide products with high added value, such as sportswear and other technical applications related to any living organism, human, animal or plant (Smart Agro).

[0041] It should be noted that any embodiment disclosed herein with respect to a product or method of manufacture according to the first or second aspect of the present invention may be used alone or in combination with any other embodiment disclosed herein, unless the context indicates otherwise.

[0042] Below are some examples which are intended to illustrate the invention and in no way limit the scope of the invention as established by the appended claims. EXAMPLES

[0043] [General synthesis procedure] Triblock copolymers were synthesized in two steps. First, PML was obtained by enzymatic ring-opening polymerization (e-ROP) of macrolactone (ML) in bulk using 1,4-butanediol as initiator. Then, in a second step, PML was used as a macroinitiator for ROP of lactide in bulk catalyzed by tin(II) 2-ethylhexanoate. Alternatively, random or block copolymers of PML and polyesters can be prepared by ROP or polycondensation methods in single or sequential polymerizations, respectively. Furthermore, triblock copolymers can be functionalized with hydroxyl (-OH), carboxyl (-COOH) or amine (-NH2) moieties. Functionalization can be performed on the end groups using carbodiimide chemistry or on the double bonds of the PML blocks by thiol-ene "click" chemistry.

[0044] [Polymacrolactone] PML with molecular weights (Mn) ranging from 10 to 25 kg / mol was obtained from unsaturated MLs such as globalide (GL) and 6-ω-hexadecene lactone (6HDL). Figure 1 shows the synthetic routes to obtain both PMLs. e-ROP was carried out in bulk under an inert atmosphere. The catalyst was Candida antarctica lipase B (CALB) enzyme and the initiator was 1,4-butanediol. The amount of enzyme was kept constant at 5 wt% in all experiments, while the amount of initiator was changed depending on the desired Mn. Alternatively, random copolymers containing PML and polyesters can be prepared in a single step by ROP or polycondensation.

[0045] [PLA-PML-PLA triblock copolymer] A series of triblock copolymers were synthesized following a single reaction pathway shown in Figure 2. Either PGL or P6HDL was used as the macroinitiator, and L-lactide or a racemic mixture (L-lactide + D-lactide) was used as the comonomer. The ROP of lactide was carried out in bulk at 180 °C under an inert atmosphere using 0.05 wt% tin(II) 2-ethylhexanoate as the catalyst. Furthermore, by varying the composition of PML and lactide, a variety of polymers with a wide range of properties were obtained. Alternatively, the macroinitiators could be random or block copolymers of either PGL or P6HDL and polyesters. The random copolymer macroinitiators could be prepared by ROP of cyclic esters with GL or 6HDL, or by polycondensation of GL or 6HDL, diols, and dicarboxylic acid derivatives. On the other hand, the block copolymer macroinitiators could be prepared by ROP of cyclic esters using PGL or P6HDL as the macroinitiator, or by polycondensation of carboxylic acid derivatives using PGL or P6HDL as the comonomer. Additionally, triblock copolymers can be functionalized with end groups using carbodiimide chemistry or with double bonds using thiol-ene "click" chemistry. Functionalization may include the use of hydrophilic or biologically active molecules such as PEG or peptides.

[0046] [purification] At the end of each polymerization, the reaction mixture was dissolved in chloroform and precipitated with cold methanol to remove unreacted monomer and catalyst, the precipitate was then filtered, washed repeatedly with fresh solvent, and dried under vacuum for 48 h.

[0047] Below are three non-limiting synthetic examples including L-lactide, D,L-lactide, globalide and 6-ω-hexadecene lactone.

[0048] Example 1 (PLLA 104 -PGL 106 -PLLA 104 Preparation of triblock copolymers The copolymer was prepared in two steps. First, polyglobalide (PGL) was synthesized by bulk enzymatic ring-opening polymerization (e-ROP) at 80 °C in a Schlenk tube. N2 gas was flowed through the tube equipped with a magnetic stirrer to create an inert atmosphere. The reactor was heated to 80 °C, and 5 w / w% Candida antarctica lipase B (CALB) enzyme and 0.95 mol% 1,4-butanediol were added. After closing the tube with a septum and stopping the N2 gas, the monomer globalide (2 g) was injected to start the polymerization. The total reaction time was 5 h. The reaction product was then dissolved in chloroform and filtered to remove the enzyme. The filtrate was then precipitated with excess methanol and washed repeatedly with fresh solvent. Finally, it was dried in vacuum at room temperature for 48 h. The molecular weight of the obtained PGL was 1 H NMR determined it to be 24.6 kg / mol. DSC study showed a melting point of 48°C and a crystallization temperature of 32°C.

[0049] PGL was then used as a macroinitiator for lactide ROP. A 50 mL three-neck reactor equipped with a mechanical stirrer was heated to 80°C and evacuated at 20 mbar for 15 min. PGL (2.5 g) and L-lactide (1.5 g) were then fed into the reactor, assisted by N2 gas to maintain an inert atmosphere. A vacuum of 50 mbar was again applied for 15 min. The pressure was returned to 1 bar and the temperature was raised to 180°C. At that temperature, stannous octoate was added at 0.05 w / w% with respect to lactide to initiate the copolymerization. The total reaction time was 2 h. The resulting polymer was dissolved in chloroform and precipitated with excess methanol. The precipitated copolymer was dried under vacuum for 48 h. The formation of the triblock was confirmed by: 1 The copolymer was confirmed by H NMR. GPC showed a number average molecular weight (Mn) of 34.2 kg / mol and a weight average molecular weight (Mw) of 66.5 kg / mol. DSC showed two melting peaks at 46.0 °C (PGL block) and 159.8 °C (PLLA block). The PGL block crystallized at 27.4 °C and -7.2 °C, while the PLLA block could not crystallize from the molten state. The copolymer showed elastic behavior in tensile tests, with an elongation at break of 250%, an elastic modulus of 158 MPa, and an ultimate tensile strength of 4.58 MPa.

[0050] Example 2 (PDLLA 139 -PGL 85 -PLLA 139 Preparation of triblock copolymers The copolymer was prepared in two steps. First, polyglobalide (PGL) was synthesized by bulk enzymatic ring-opening polymerization (e-ROP) at 80 °C in a Schlenk tube. N2 gas was flowed through the tube equipped with a magnetic stirrer to create an inert atmosphere. The reactor was heated to 80 °C, and 5 w / w% Candida antarctica lipase B (CALB) enzyme and 1.18 mol% 1,4-butanediol were added. After closing the tube with a septum and stopping the N2 gas, the monomer globalide (2 g) was injected to start the polymerization. The total reaction time was 5 h. The reaction product was then dissolved in chloroform and filtered to remove the enzyme. The filtrate was then precipitated with excess methanol and repeatedly washed with fresh solvent. Finally, it was dried in vacuum at room temperature for 48 h. The molecular weight of the obtained PGL was 1 It reached 21.5 kg / mol as determined by 1 H NMR.

[0051] PGL was then used as a macroinitiator for lactide ROP. A 50 mL three-neck reactor equipped with a mechanical stirrer was heated to 80°C and evacuated at 20 mbar for 15 min. PGL (2.0 g) and D,L-lactide (2.0 g) were then fed into the reactor, assisted by N2 gas to maintain an inert atmosphere. A vacuum of 50 mbar was again applied for 15 min. The pressure was returned to 1 bar and the temperature was raised to 180°C. At that temperature, stannous octoate was added at 0.05 w / w% with respect to lactide to initiate the copolymerization. The total reaction time was 2 h. The resulting polymer was dissolved in chloroform and precipitated with excess methanol. The precipitated copolymer was dried under vacuum for 48 h. The formation of the triblock was confirmed by: 1 The copolymer was confirmed by H NMR. The number average molecular weight (Mn) was 37.0 kg / mol, and the weight average molecular weight (Mw) was 65.4 kg / mol as measured by GPC. The copolymer showed only one melting peak at 41.0 °C due to the PGL block, which crystallized in two steps at 23.1 °C and -3.9 °C. The PDLLA block was amorphous. The copolymer showed elastic behavior in tensile tests, with an elongation at break of 230%, an elastic modulus of 553 MPa, and an ultimate tensile strength of 11.9 MPa.

[0052] Example 3 (PLLA 208 -P6HDL 42 -PLLA 208 Preparation of triblock copolymers The copolymer was prepared in two steps. First, polyglobalide (PGL) was synthesized by bulk enzymatic ring-opening polymerization (e-ROP) at 80 °C in a Schlenk tube. N2 gas was flowed through the tube equipped with a magnetic stirrer to create an inert atmosphere. The reactor was heated to 80 °C, and 5 w / w% Candida antarctica lipase B (CALB) enzyme and 2.36 mol% 1,4-butanediol were added. After closing the tube with a septum and stopping the N2 gas, the monomer 6-ω-hexadecene lactone (2 g) was injected to start the polymerization. The total reaction time was 5 h. The reaction product was then dissolved in chloroform and filtered to remove the enzyme. The filtrate was then precipitated with excess methanol and repeatedly washed with fresh solvent. Finally, it was dried in vacuum at room temperature for 48 h. The molecular weight of the obtained P6HDL was 1 It reached 10.5 kg / mol as determined by 1 H NMR.

[0053] P6HDL was then used as a macroinitiator for lactide ROP. A 50 mL three-neck reactor equipped with a mechanical stirrer was heated to 80°C and evacuated at 20 mbar for 15 min. P6HDL (1.0 g) and L-lactide (3.0 g) were then fed into the reactor, assisted by N2 gas to maintain an inert atmosphere. A vacuum of 50 mbar was again applied for 15 min. The pressure was returned to 1 bar and the temperature was raised to 180°C. At that temperature, stannous octoate was added at 0.05 w / w% with respect to lactide to initiate the copolymerization. The total reaction time was 2 h. The resulting polymer was dissolved in chloroform and precipitated with excess methanol. The precipitated copolymer was dried under vacuum for 48 h. The formation of the triblock was confirmed by: 1The copolymer was confirmed by H NMR. The number average molecular weight (Mn) reached 43.0 kg / mol and the weight average molecular weight (Mw) reached 68.0 kg / mol as measured by GPC. The copolymer showed two melting peaks at 44.5 °C (P6HDL block) and 1636 °C (PLLA block). The PGL block crystallized at -10.4 °C, whereas the PLLA block crystallized at 99.8 °C. The copolymer showed elastic behavior in tensile tests, with an elongation at break of 34%, an elastic modulus of 491 MPa, and an ultimate tensile strength of 25.5 MPa.

[0054] Example 4 (COOH-PEG 24 -PDLLA 139 -PGL 85 -PDLLA 139 -PEG 24 Synthesis of -COO triblock copolymer PEG-functionalized triblock copolymers were prepared by combining triblock copolymers with carboxyl-terminated PEG (COOH-PEG 24 As an example, the triblock copolymer PDLLA was prepared as described in Example 2 by esterification with 1,4-dichlorophenyl triblock copolymer (PDLLA-1, PDLLA-2, PDLLA-3, PDLLA-4, PDLLA-5, PDLLA-6, PDLLA-7, PDLLA-8, PDLLA-9, PDLLA-10, PDLLA-11, PDLLA-12, PDLLA-13, PDLLA-14, PDLL 139 -PGL 85 -PDLLA 139 A mixture containing DCC (3.00 g, 0.075 mmol) and a 5-fold excess of carboxyl-terminated PEG (Mn = approx. 1,000 g / mol, 0.75 g, 0.75 mmol) was added to a round-bottom flask equipped with a magnetic stirrer. The mixture was dissolved in 20 mL of DCM for 30 min. DCC (0.774 g, 3.75 mmol) and DMAP (0.018 g, 0.15 mmol) were then added to the solution and the reaction was allowed to proceed at room temperature for 24 h. The reaction mixture was then poured into an excess of cold methanol. The precipitate was filtered, washed repeatedly with fresh methanol and cold diethyl ether (-18 °C) to remove the methanol, dried under vacuum for 48 h, and stored in a desiccator until further use.

[0055] Esterification of triblock copolymers with carboxyl-terminated PEG 1The yield was 95% as determined by H NMR. The number-average and weight-average molecular weights were Mn=37 kg / mol and Mw=65 kg / mol, respectively. The contact angle of the PEG-functionalized triblock copolymer decreased from 90° to 86° upon the addition of PEG. Furthermore, the elongation at break increased from 230% to 380% with the addition of PEG, while the ultimate tensile strength and modulus decreased from 11.9 MPa to 4.4 MPa and from 553 MPa to 140 MPa, respectively.

[0056] [Other Examples and Results] Up to 12 syntheses were carried out to verify the properties of the triblock copolymers following the same methodology described in Examples 1, 2, and 3. Table 1 lists all the synthesized triblock copolymers, grouped by PLA and PML composition.

[0057] [Table 1]

[0058] In all cases, the monomer-to-polymer conversion was over 90%, and the triblock copolymer was recovered in high yield (>85%). The theoretical molecular weight for an ideal reaction was targeted to be 40 kg / mol. Furthermore, since copolymers with different PLA / PML compositions were planned, the block lengths of PLA (segment A) and PML (segment B) were adjusted proportionally. The compositions and molecular weights of the triblock copolymers were: 1 The PLA composition was calculated by H NMR and GPC. Table 1 shows that copolymers with PLA compositions in the range of 50-90 mol% were obtained. Furthermore, the molecular weights were between 30 and 40 kg / mol. Some samples had slightly lower molecular weights, which was probably due to the presence of unwanted hydroxyl or carboxyl initiation species in the reaction system. On the other hand, the deviations in the PLA composition were due to the loss of lactide by anti-sublimation before the start of the reaction. The loss (in milligrams) was almost constant, but when a lower lactide content was used, the loss became more significant.

[0059] Nevertheless, the triblock structure 1 H and 13 This was confirmed by C NMR. 174 -PGL 63 -PLLA 174 of 1 The H NMR spectrum is shown. The peak identification confirmed the reaction between PML and lactide and the triblock structure. The methane (i), methyl (h) and -(CH3)CH-OH end group (h') concentrations of the PLA block were detected at 1.59, 5.17 and 4.35 ppm, respectively. The long methylene sequence (e), methine (d, d'), methylenes around the unsaturation (c, c'), methylenes adjacent to the ester group (a, g) and the next methylene group (b, f) were detected at 1.28, 5.40, 2.01, 4.07, 2.29 and 1.69 ppm, respectively. Furthermore, as shown in Figure 4, 13 The C spectrum showed that neither transesterification nor racemization occurred during the polymerization. The peaks of PLLA and PML appearing in the carbonyl region (169–175 ppm) were singlets, which meant that each polyester block was distinct.

[0060] Table 2 shows the mechanical properties of triblock copolymers. These results prove that the block length plays an important role. A neat PLLA film that reproduced the molecular weight of the copolymer (40 kg / mol) was too brittle to obtain a sample for testing. On the other hand, even copolymers with PML of 9-10 mol% showed improved mechanical performance compared to PLLA. In general, the elongation at break (ε b ) was obviously improved with increasing PML, but at the same time, the ultimate tensile strength (σ max ) and elastic modulus (E) decreased. Thus, by simply adjusting the PLA / PML composition, PLA-based materials with tunable properties from stiff to ductile could be prepared.

[0061] [Table 2]

[0062] Because neat PLLA with a molecular weight of 40 kg / mol was too brittle to test, PLLA with higher molecular weight (Mn=72 kg / mol, Mw=144 kg / mol) was synthesized. Figure 5 shows the cross-sectional structure of high molecular weight PLLA and triblock copolymer PDLLA. 104 -PGL 106 -PDLLA 104 The results of tensile strength tests performed on the triblock structures with PML in the middle block show ductile behavior.

[0063] The composition of the triblock structure is determined by the melting point (T m ) of the respective blocks. Table 3 summarizes the thermal properties of the triblock copolymers. As the composition of either PML or PLA increases, the T m The number of cases also increased. m The difference between the Tg and the degradation onset temperature at 5% (°T d,5% ) and residual weight (R w ) did not show any significant changes.

[0064] [Table 3]

[0065] Thermal characterization also confirmed the triblock structure. Figure 6 shows the first cooling and heating traces of the DSC at 10 °C / min after removing the thermal history of the sample. Each polyester maintains its thermal behavior, thereby increasing the T m and T g was identified.

[0066] PDLLA 139 -PGL 85 -PDLLA 139 The PEG functionalization of the PEG-based polymer was successfully performed as shown in Figure 7. 1 Comparison of H NMR spectra confirmed the esterification of the COOH-PEG-COOH triblock copolymer. 24The -COOH was removed by precipitation in methanol, leaving only the PEG chains attached to the triblock copolymer. The number of PEG repeat units attached to the triblock copolymer was 1 The molecular weights were calculated from the integrals of peaks (c) in the H NMR spectrum. They matched the number of repeating units (24) given by the donor, so essentially complete esterification was achieved. Furthermore, the number-average and weight-average molecular weights were Mn = 37 kg / mol and Mw = 65 kg / mol, respectively. These values ​​were consistent with those of the triblock copolymer PDLLA. 139 -PGL 85 -PDLLA 139 The molecular weight of PEG was approximately 1 kg / mol, which was a reasonable value.

[0067] The contact angle of the PEG-functionalized triblock copolymer decreased from 90° to 86° with the addition of PEG. This small decrease in contact angle was essential to change the triblock copolymer surface from relatively hydrophobic (above 90°) to hydrophilic (below 90°). The effect of the small change was more pronounced when comparing rough surfaces, since roughness enhances the hydrophobic or hydrophilic nature of the flat surface. Figure 8 compares the change in the water droplet on the rough surface of the triblock copolymer scaffold before and after PEG functionalization. The contact angle of the relatively hydrophobic triblock copolymer increased from 90° to 114° with the increase in roughness. Moreover, the water droplet did not move during the 120 s experiment. In contrast, the hydrophilic PEG-functionalized copolymer scaffold showed a decrease in contact angle from 86° to 74° compared to the flat film. In fact, the water droplet gradually decreased its contact angle over time and virtually disappeared from the scaffold surface.

[0068] In terms of mechanical properties, the PEG-functionalized copolymers exhibited more ductile and flexible properties compared to the neat triblock copolymer. Figure 9 shows the mechanical properties of PDLLA before and after PEG functionalization. 139 -PGL 85 -PDLLA 139Figure 1 shows a typical stress-strain curve under tensile load of 1000 MPa. Due to the plasticizing effect of the PEG chains, the breaking elongation increased from 230% to 380%. At the same time, the elastic modulus and ultimate tensile strength decreased from 553 MPa to 140 MPa and from 11.9 MPa to 4.4 MPa, respectively.

[0069] Characterization All synthesized PLA-PML-PLA were analyzed using the following techniques. Nuclear magnetic resonance (NMR): 1 H and 13 C spectra were obtained at 25 °C using a Bruker AMX-300 at frequencies of 300.1 MHz and 75.5 MHz, respectively. 1 64 scans were performed for the H spectrum. 13 The C spectrum was scanned 1,000 to 10,000 times. 1 10 mg for H spectrum, 13 For C spectra, 50 mg of the sample was dissolved in deuterated chloroform (CDCl3). Tetramethylsilane (TMS) was used as the internal standard. In addition, in some cases, homonuclear 1 H- 1 H(COSY) and heteronuclear correlations 1 H- 13 Two-dimensional spectroscopy such as C(HETCOR) was applied. Gel Permeation Chromatography (GPC): Molecular weights were determined by GPC using a Waters instrument. Two columns and two different eluents were used depending on the polymer sample. The eluents were hexafluoroisopropanol (HFIP) and tetrahydrofuran (THF). Molecular weights were calculated relative to polymethylmethacrylate (PMMA) in HFIP and polystyrene (PS) in THF standards. Samples were prepared by dissolving 1 mg of polymer in 1 mL of solvent. Measurements were performed at 35 °C. Differential Scanning Calorimetry (DSC): Thermal transitions were evaluated by calorimetric scans performed on a Perkin-Elmer Pyris 1 and DSC 8500. Thermograms were recorded from 4–6 mg of polymer under a continuous nitrogen flux of 20 mL / min. Standards used for temperature and enthalpy calibration were indium and zinc. Thermogravimetric analysis (TGA): The thermal stability of the polymer was tested in the temperature range of 50-600° C. The analysis was carried out on a Mettler-Toledo TGA / DSC 1 Star system using nitrogen flux at a heating rate of 10° C. / min. Tensile test: Mechanical testing was performed on a 500N zwicki instrument from Zwick Roell. Tensile and elongation data were recorded by testXpert® III software. Testing was performed according to the ISO 527-2 standard using 5B standard specimens obtained from polymer films. Contact angle (CA): Droplet shape analysis with stationary water droplets was performed with an OCA 20 (DataPhysics Instruments GmbH, Filderstadt) and SCA20 software. CAs were 3 × 1 cm 2 The measurements were taken 5 seconds after dropping 0.500 μL of distilled water onto the film samples at room temperature. The left and right CA values ​​were measured and averaged. At least 10 measurements were performed on three different film polymer samples. Dynamic CA measurements were also performed by taking pictures of the water droplets at scheduled times.

Claims

1. The following structure (I): Polylactic acid (PLA)-X-polylactic acid (PLA) (I) [In the formula, X is an unsaturated polymacrolactone (PML) or a copolymer comprising PML and a polyester. A triblock copolymer comprising:

2. The following structure (I): Polylactic acid (PLA)-X-polylactic acid (PLA) (I) [In the formula, X is an unsaturated polymacrolactone (PML) or a copolymer comprising PML and a polyester. The triblock copolymer according to claim 1, consisting of

3. 2. The triblock copolymer of claim 1, wherein the PML is selected from polyglobalide (PGL), poly(ambrettolide) (PAmb), poly(6-ω-hexadecene lactone) (P6HDL), and combinations thereof.

4. 2. The triblock copolymer of claim 1, wherein the polyester is selected from polypentadecalactone (PPDL), polycaprolactone (PCL), polyglycolic acid (PGA), poly(paradioxanone), and combinations thereof.

5. 10. The compound according to claim 1, having the following structure (I): Polylactic acid (PLA)-X-polylactic acid (PLA) (I) [In the formula, X is an unsaturated polymacrolactone (PML) or a copolymer comprising PML and a polyester.

1. A method for producing a triblock copolymer comprising: (a) preparing an unsaturated polymacrolactone (PML) by ring-opening polymerization (ROP) of the corresponding unsaturated macrolactone (ML) using a diol as an initiator; Here, when X is a copolymer containing PML and polyester, after the step (a) and before the next step (c), the following step: (b-i) when the polyester is derived from a cyclic ester monomer, preparing a copolymer comprising PML and a polyester by ring-opening polymerization (ROP) of the cyclic ester monomer using the unsaturated PML obtained in step (a) as a macroinitiator; or (b-ii) if the polyester is derived from an acyclic ester monomer, there is an additional step (b) comprising: preparing a copolymer comprising PML and a polyester by polycondensation of the acyclic ester monomer using the unsaturated PML obtained in step (a) as a comonomer, (c) polymerizing lactide by ring-opening polymerization (ROP) using the unsaturated polymacrolactone obtained in step (a) or the copolymer obtained in step (b) as a macroinitiator and tin(II) 2-ethylhexanoate as a catalyst; A method for producing a triblock copolymer, comprising:

6. 10. The compound according to claim 1, having the following structure (I): Polylactic acid (PLA)-X-polylactic acid (PLA) (I) [In the formula, X is a copolymer containing PML and polyester. A method for obtaining a triblock copolymer having the following structure: (1a) preparing a copolymer of PML and polyester by ring-opening polymerization (ROP) of the corresponding unsaturated macrolactone (ML) with a cyclic ester using a diol as an initiator; or (1b) if the comonomer is not a cyclic ester, preparing a copolymer of PML and polyester by polycondensation of the corresponding ML with a diol and a dicarboxylic acid or derivative; (2) using the unsaturated polymacrolactone obtained in step (1a) or (1b) as a macroinitiator and tin(II) 2-ethylhexanoate as a catalyst to polymerize lactide by ring-opening polymerization (ROP); A method comprising:

7. When the triblock copolymer is end-functionalized, the hydroxyl (—OH) end groups of the triblock copolymer are converted to carboxyl (—COOH) or amine (—NH) groups by carbodiimide chemistry. ２ ) group; or - if the triblock copolymer is grafted, reacting the double bonds of the PML blocks with thiol-containing molecules by thiol-ene "click" chemistry; or - if the triblock copolymer is crosslinked, reacting the double bonds of the PML blocks with each other or with other crosslinking molecules, The method of claim 5 or 6, further comprising:

8. 7. The method of claim 5 or 6, wherein the PML is selected from polyglobalide (PGL), poly(ambrettolide) (PAmb), poly(6-ω-hexadecene lactone) (P6HDL), and combinations thereof.

9. 7. The method of claim 5 or 6, wherein the polyester is selected from polypentadecalactone (PPDL), polycaprolactone (PCL), polyglycolic acid (PGA), poly(paradioxanone), and combinations thereof.

10. The method according to step (c) of claim 5 or step (2) of claim 6, wherein the lactide is L-lactide or a mixture of L-lactide and D-lactide.

11. 10. The method of claim 5, step (a) or claim 6, step (1a) or (1b), wherein the step is carried out using a catalyst.

12. The method according to step (c) of claim 5 or step (2) of claim 6, wherein the step is carried out in bulk under an inert atmosphere at 120-190°C.

13. 7. The method according to claim 5 or 6, wherein the concentration of the tin(II) 2-ethylhexanoate is 0.025 to 0.10% by weight.

14. 7. The process of claim 5 or 6, wherein at the end of each polymerization, unreacted monomer is removed and the catalyst is removed or deactivated.

15. Use of the triblock copolymer according to any one of claims 1 to 4, a) medical devices for tissue regeneration; b) Medical devices for drug delivery systems; c) Lab-on-a-chip and organ-on-a-chip devices; d) Hydrogels for health and smart agriculture applications; e) sensors, biosensors and electrodes; f) electronic equipment; g) packaging films and trays; h) textiles and synthetic leather; i) coating and surface protection solutions, or j) Masterbatch or blend compatibilizing additives Use of the triblock copolymer for the preparation of a polymerizable compound.

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