Multiblock Copolymer Composition

Abstract

A method for producing multi-block copolymers that reduces the tendency to form large phase domains provides copolymer compositions that are useful in a variety of applications, including the manufacture of medical devices.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 715,978, filed Aug. 8, 2018, the entirety of which is incorporated herein by reference. ·background Field

[0002] The present application relates to multi-block copolymers and methods of making the same that reduce or eliminate the tendency of copolymer compositions to contain large phase domains, as well as medical devices containing such materials. Description of Related Art [Background technology]

[0003] A number of copolymers have been developed for medical applications, including those described in U.S. Patent Nos. 8,252,887; 8,476,399; 8,551,511; and 9,416,090, as well as those described in U.S. Patent Application Publication No. 2015 / 0045451. Some of the copolymer compositions described in these patent publications exhibit a degree of phase separation that enhances mechanical properties such as fracture and / or fatigue toughness. See, for example, U.S. Patent No. 8,551,511. The disclosures of U.S. Pat. Nos. 8,252,887, 8,476,399, 8,551,511, and 9,416,090, and U.S. Patent Application Publication No. 2015 / 0045451, are incorporated herein by reference, and are specifically incorporated herein for the purposes of describing the copolymer compositions and methods of making the same described therein. Summary of the Invention [Problem to be solved by the invention]

[0004] ·overview It has now been discovered that certain aspects of multi-block copolymer phase separation can detrimentally affect the properties of copolymer compositions, particularly in compositions including multi-block copolymers that have a strong tendency to form large discontinuous domains of a first polymer phase dispersed in a continuous second polymer phase. For example, it has now been found that certain copolymer compositions, exemplified by that described in Example 21 of U.S. Pat. No. 9,416,090, have morphologies characterized by undesirably large discrete phase domains, as shown in FIG. Traditionally, such morphology was believed to be the result of the relative amounts of diol comonomers copolymerized with triphosgene (a source of phosgene) to produce the multiblock copolymer. Thus, even if the copolymerization of a selected combination of comonomers yielded a balance of desirable properties in the resulting multiblock copolymer itself, the morphology (e.g., phase structure) of the copolymer composition at thermodynamic equilibrium was thought to be determined by its chemical composition and therefore difficult to meaningfully alter.

[0005] Surprisingly, it has now been found that the morphology of a copolymer composition can be enhanced by controlling the make up of its multi-block copolymer components. For example, a multi-block copolymer made from the same combination of comonomers as in Example 21 of US Pat. No. 9,416,090 can be made to have a copolymer composition morphology with preferably smaller discontinuous domains, as illustrated in Figure 2, or a copolymer composition morphology with substantially no phase separation, as illustrated in Figure 3, according to the teachings described herein.

[0006] Accordingly, various embodiments provide such copolymer compositions, methods for their preparation, and medical devices comprising such copolymer compositions, as described in more detail below. [Means for solving the problem]

[0007] One embodiment provides a copolymer composition comprising:

[0008] A copolymer composition comprising a multi-block copolymer including a first block and a second block, the first block is substituted with heavy atoms in an amount effective to render it more radiopaque than the second block, and the multi-block copolymer has a number average molecular weight of 100 kDa or greater;

[0009] the multi-block copolymer is in a single phase form having a single phase glass transition temperature greater than 37° C.; or

[0010] the copolymer composition comprises a discontinuous first polymer phase having a first glass transition temperature greater than 37° C. and a continuous second polymer phase having a second glass transition temperature greater than 37° C.; the discontinuous first polymer phase being relatively concentrated in a first block of a multi-block copolymer; The continuous second polymer layer is concentrated relative to the second block of the multi-block copolymer.

[0011] In another embodiment, there is provided a method for making the copolymer composition described herein, comprising copolymerizing an aromatic diol monomer of Formula (A1a) and an aliphatic diol monomer of Formula (B1a) in the presence of a phosgene source under selected reaction conditions to form a multi-block copolymer.

[0012] Another embodiment provides an implantable medical device (such as a stent) comprising a copolymer composition as described herein.

[0013] These and other embodiments are described in further detail below. [Brief description of the drawings]

[0014] FIG. 1 is a scanning electron microscope (SEM) photograph of the multiblock copolymer of Comparative Example 1, illustrating phase separation between large discontinuous domains 110 of a first polymer phase (relatively concentrated in blocks of PrD-diI2DAT) dispersed in a continuous second polymer phase (relatively concentrated in blocks of EGPLLAD7k).

[0015] FIG. 2 shows an SEM photograph of the multi-block copolymer of Example 2, illustrating the phase separation between smaller (compared to FIG. 1 ) discontinuous domains 210 of the first polymer phase (relatively enriched in blocks of PrD-diI2DAT) dispersed in a continuous second polymer phase (relatively enriched in blocks of EGPLLAD7k).

[0016] FIG. 3 shows an SEM photograph of the multiblock copolymer of Example 3, demonstrating the lack of phase separation between the blocks of PrD-diI2DAT and EGPLLAD7k (at this magnification by SEM).

[0017] 4A, 4B, and 4C show aspects of the copolymerization reaction kinetics between phosgene (COCl2) and comonomers of formulas (A1a) and (B1a).

[0018] FIG. 5 shows Table 1 showing the densities and corresponding SEM images of examples of multi-block copolymers. Detailed Description definition DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] As used herein, the term "glass transition temperature" has its ordinary meaning as understood by one of skill in the art, and thus refers to the temperature at which a polymeric material or phase undergoes a second order thermal transition from a glassy state to a rubbery state as determined by differential scanning calorimetry (DSC).

[0020] The term "heavy atom" as used herein has its ordinary meaning as understood by those of skill in the art in the context of describing the atom that confers radioactivity to the polymer, and thus includes bromine and iodine.

[0021] As used herein, the term "medical device" has its ordinary meaning as understood by those of skill in the art, and thus includes products that meet the U.S. Food and Drug Administration (FDA) definition of a medical device as set forth in Section 201(h) of the Federal Food, Drug, and Cosmetic Act.

[0022] As used herein, the term "multi-block copolymer" has its ordinary meaning as understood by one of ordinary skill in the art and thus includes copolymers that contain two or more different homopolymeric subunits that are covalently linked.

[0023] As used herein in the context of describing chemical structures, "organic spacer," "organic spacer group," "linking group," and similar terms have their ordinary meanings as understood by those of skill in the art, and thus include generally linear groups containing any number of carbon atoms ranging from 1 to 30, and attached to the remainder of the chemical structure at two or more points, typically terminally. In various embodiments, the number of carbon atoms in the organic spacer group can be any integer within the range of 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-15, 1-20, 2-4, 2-6, 2-8, 2-10, 2-12, 2-15, 2-20, 2-30, 4-6, 4-8, 4-10, 4-12, 4-15, 4-20, 4-30, or 7-18. Non-limiting examples of organic spacer groups include C 1-30 Alkylene (e.g., -(CH2) 1-30 -), C 2-30 Oxyalkylene (e.g., -(CH2CH2O) 1-15 -), C 1-30Diols (e.g. -O-(CH2) 1-30 -O-), C 4-30 Dicarboxylene (e.g., -O-(C=O)-(CH2) 2-28 -(C=O)-O- and -(C=O)-O-(CH2) 2-28 -O-(C=O)-), C 8-30 Diester alkylene (e.g., -CH2CH2-O-(C=O)-(CH2) 2-24 -(C=O)-O-CH2CH2- and -CH2CH2-(C=O)-O-(CH2) 2-24 -O-(C=O)-CH2CH2-), C 4-30 Diamide alkylene (e.g., -NH-(C=O)-(CH2) 2-28 -(C=O)-NH- and -(C=O)-NH-(CH2) 2-28 -NH-(C=O)-), C 4-30 Dicarbonate alkylene (e.g., -O-(C=O)-O-(CH2) 2-28 -O-(C=O)-O-) and C 2-30 Oxyalkylenediol (e.g., -O-(CHO) 2-30 -) are mentioned. Those skilled in the art will recognize that the examples of organic spacer groups listed above are within a certain range (e.g., C 1-30 ), it will be appreciated that the number of carbon atoms is not so limited and thus such examples of organic spacer groups can include various ranges of numbers of carbon atoms as described in this paragraph or elsewhere herein. For example, in one embodiment, the organic spacer group has the formula -CH2CH2-(C=O)-O-(CH2) a1 It is a diester alkylene of -O-(C=O)-CH2CH2-, where a1 is in the range of 1 to 12.

[0024] As used herein, "phase separated," "phase separation," and similar terms have their ordinary meanings as understood by those of skill in the art, and thus include reference to a polymer composition that includes two or more polymeric regions that are immiscible with each other to the extent that the separated regions can be detected by scanning electron microscopy (SEM) and / or DSC. For example, a phase-separated multi-block copolymer contains separate regions that are each relatively enriched in one or another of the different homopolymeric subunits contained in the copolymer. In some cases, imaging of separated phases by SEM can be assisted by elemental analysis techniques known to those skilled in the art, such as energy dispersive X-ray spectroscopy (EDS). In many cases, SEM and DSC are particularly effective when used together to detect phases in phase-separated multi-block copolymers. Copolymer Composition

[0025] It has now been discovered that certain copolymer compositions have a morphology characterized by large discrete phase domains 110, as shown in FIG. For example, scanning electron microscopy (SEM) shows that the copolymer composition of Comparative Example 1 below, prepared as described in Example 21 of U.S. Pat. No. 9,416,090, contains a first polymer phase (relatively enriched in units of PrD-diI2DAT) in the form of large discontinuous domains 110 dispersed in a continuous second polymer phase (relatively enriched in units of EGPLLAD7k). Surprisingly, the average size of the large discrete phase domains 110 was about 15 μm, indicating that the multiblock copolymer formed by the process of Example 21 of U.S. Pat. No. 9,416,090 was highly blocked, containing relatively long sequences concentrated in blocks of EGPLLAD7k as well as relatively long sequences concentrated in blocks of PrD-diI2DAT.

[0026] As shown in Comparative Example 1 below, a multi-block copolymer formed by the process of Example 21 of US Pat. No. 9,416,090 had a number average molecular weight of about 75 kDa. Therefore, the morphology shown in FIG. 1 is not driven by phase separation of low molecular weight oligomers. Those skilled in the art understand the relationship between time and degree of polymerization in the context of step polymerization kinetics. In particular, the average molecular weight increases relatively slowly during the step polymerization as monomers react with each other to form dimers, dimers react with monomers to form trimers, and dimers react with dimers to form tetramers. Thus, significant amounts of high molecular weight polymer are generally not formed in step polymerizations until the final stages of the reaction, at which point low molecular weight oligomers are at very low levels. It is also important to note that the multiblock copolymer of Example 21 of U.S. Pat. No. 9,416,090 was prepared under uncontrolled temperature conditions without rigorous drying of the initial monomers.

[0027] Those skilled in the art also understand that high molecular weight polymers will not be formed from reactions between difunctional monomers (e.g., reactions between AA and BB comonomers where functional group A reacts only with functional group B) unless the reaction stoichiometry is precisely controlled so that the molar ratio of reacting functional groups is as close to 1:1 as practical. Thus, for example, in the reaction between a diol (eg, HO-R-OH) and phosgene (Cl-CO-Cl) to form a polycarbonate, high molecular weights are achieved by careful stoichiometric control. A slight excess of diol gives a relatively low molecular weight mixture of various hydroxy-terminated oligomers, and a slight excess of phosgene gives a similar mixture of oligomers, but end-capped with chloroformate groups. In such polymerizations, diols cannot be linked together without phosgene, and vice versa, so one or the other block cannot be easily formed by manipulating the reaction conditions, such as by using an excess of one monomer or the other.

[0028] The step polymerization reaction described in Example 21 of U.S. Pat. No. 9,416,090 illustrates the copolymerization of monomers containing multiple functional groups of differing reactivity, specifically triphosgene (a phosgene source) and two diols (PrD-diI2DAT and EGPLLAD). Those skilled in the art will appreciate that the step polymerization kinetics for reactions between monomers containing multiple functional groups of differing reactivity are much more complex than when only difunctional monomer pairs are involved. Thus, except for very well understood step polymerizations (typically those of commercial or academic interest), there is generally little or no expectation that one can control the sequence distribution or blockiness of copolymers by manipulating the reaction conditions for the step polymerization of three or more different comonomers with functional groups of differing reactivity. Thus, the surprising degree of blockiness discovered for the multi-block copolymers formed by the process of Example 21 of US Pat. No. 9,416,090 was unexpected.

[0029] Copolymer compositions have now been developed that exhibit smaller domain sizes indicative of a lower degree of blockiness. For example, Figure 2 shows an SEM photograph of the multi-block copolymer of Example 2, which illustrates phase separation in the form of smaller discontinuous domains 210, as compared to Figure 1, and Figure 3 shows an SEM photograph of the multi-block copolymer of Example 3, which illustrates the lack of visible phase separation at this SEM magnification, as compared to Figures 1 and 2. As described below, the multi-block copolymers of Examples 2 and 3 were prepared using the same amounts of monomers used to prepare the multi-block copolymer of Comparative Example 1. Thus, the copolymer composition of Example 2 also contains a first polymer phase (relatively enriched in PrD-diI2DAT units) in the form of discontinuous domains 210 dispersed in a continuous second polymer phase (relatively enriched in EGPLLAD7k units), but the domains 210 have an average domain size of less than 10 μm, indicating that the multiblock copolymer of Example 2 is less blocked than the multiblock copolymer of Comparative Example 1. The copolymer of Example 3 does not show visible phase separation by the SEM method used ( FIG. 3 ), indicating that the multiblock copolymer is in the form of a single phase and is even less blocky than the multiblock copolymer of Example 2. This unexpected reduction in average domain size (Figure 2) and the unexpected formation of single-phase multiblock copolymers (Figure 3) were achieved by careful selection of polymerization conditions that favored more random (and therefore less blocky) incorporation of PrD-diI2DAT and EGPLLAD7k units into the polymer.

[0030] Although the invention is not limited by theory of operation, it is believed that such polymerization conditions enhance the relative rate at which less reactive comonomers are incorporated into the polymer. A series of simplified reaction schemes illustrating the complex kinetics of such multicomponent polymerization systems are shown in Figures 4A-4C. In the illustrated system, phosgene is reacted with a mixture of aromatic diol monomers of formula (A1a) and aliphatic diol monomers of formula (B1a). Here, variable A 1 , B 1 , R 1 , X 1 , a2, m and n are described elsewhere herein. Those skilled in the art will recognize that PrD-diI2DAT is a specific example of a monomer of formula (A1a) and EGPLLAD7k (having a number average molecular weight of about 7 kDa) is a specific example of a monomer of formula (B1a). 4A-4C thus provide a simplified illustration of the reaction kinetics of the copolymerization conditions of Comparative Example 1 and Examples 2-3.

[0031] In FIG. 4A, reaction scheme (1) illustrates the reaction of monomer (A1a) with phosgene with rate constant k1 to form chloroformate monomer (A1a)-COCl. Similarly, reaction scheme (2) illustrates the reaction of monomer (B1a) with phosgene to form chloroformate monomer (B1a)-COCl with rate constant k2. As shown in FIG. 4B, each of the two chloroformate monomers, (A1a)-COCl and (B1a)-COCl, can react with additional monomers of either formula (A1a) or formula (B1a)-COCl to form carbonate dimers, (D1), (D2), (D3) and (D4), respectively, as shown by the four reaction equations (3), (4), (5) and (6) and their respective rate constants, k3, k4, k5 and k6, each having the chemical structure shown in FIG. 4C. Those skilled in the art will appreciate that the carbonate dimers (D1), (D2), (D3) and (D4) can be reacted with additional phosgene in a manner similar to that shown in equations (1) and (2) to form the corresponding chloroformate dimers, and that these chloroformate dimers can be reacted with additional monomers of either formula (A1a) or formula (B1a) to form trimers in a manner similar to that shown in equations (3), (4), (5) and (6). Finally, if the stoichiometry is properly controlled in the manner described above, the copolymerization process can proceed in a manner generally known to those skilled in the art to form high molecular weight copolymers.

[0032] One skilled in the art will appreciate that when rate constants k1 and k2 are approximately equal to one another, and when rate constants k3, k4, k5 and k6 are also approximately equal to one another, the incorporation of units corresponding to monomers (A1a) and (B1a) will be approximately random in a manner that reflects the respective monomer concentrations in the polymerization mixture. Assuming kinetic equivalence of such rate constants, the resulting block copolymers will tend to exhibit phase separation on a scale approximating the size of the (A1a) and (B1a) units in the copolymer, and will not exhibit very small domains that may be difficult to characterize by SEM, or even any phase separation at all. However, as discussed above, it has been found that multi-block copolymers formed by the process of Example 21 of U.S. Pat. No. 9,416,090 exhibit a surprising degree of blocking, as evidenced by the relatively large domains shown in FIG.

[0033] Thus, one explanation for the configuration shown in FIG. 1 is that the rate constants k1 and k2 are not approximately equal to one another, and / or the rate constants k3, k4, k5 and k6 are not approximately equal to one another. For example, if k1 is significantly greater than k2, the concentration of (B1a)-COCl will be lower, the rates of reactions (5) and (6) will be lower, the formation of carbonate dimer (D4) will be relatively slow, the formation of carbonate dimer (D1) will be relatively fast, and the blocking properties of the resulting copolymer will be greater. Similarly, if k3 is significantly larger than k4, k5, and k6, the carbonate dimer (D1) will form relatively quickly.

[0034] Given the need to incorporate the relative amounts of the two diols that yield the desired physical and mechanical properties, combined with the need for careful control of stoichiometry as discussed above, the ability to influence polymerization kinetics by adjusting monomer concentrations was thought to be limited. However, as shown in FIG. 2 and especially FIG. 3, polymerization conditions are now being developed that favor a more random (and therefore less blocky) incorporation of comonomers. For example, the process of Example 21 of U.S. Pat. No. 9,416,090 was carried out by adding triphosgene relatively slowly to a mixture of PrD-diI2DAT and EGPLLAD7k over a period of 2 to 3 hours to obtain a copolymer composition having a relatively block-like copolymer structure and a relatively large phase domain (FIG. 1). During the synthesis of the copolymer of Example 21 of U.S. Pat. No. 9,416,090, the monomers were not rigorously dried before polymerization, and the reaction temperature was not controlled. We now find that, using the same amounts of the same monomers, the addition of triphosgene relatively quickly and / or at elevated temperatures to a mixture of PrD-diI2DAT and EGPLLAD7k can produce copolymer compositions with relatively small phase domains (Figure 2), and that the more rapid addition of triphosgene to the same well-dried monomers can even produce copolymer compositions that do not show visible phase-separated domains by SEM (Figure 3). Although the invention is not limited by theory of operation, it is believed that by increasing the relative phosgene concentration, such polymerization conditions enhance the relative rate at which an aliphatic diol monomer (e.g., EGPLLAD) is incorporated into the copolymer compared to the rate at which an aromatic diol monomer (e.g., PrD-diI2DAT) is incorporated. For example, in view of the kinetic schemes illustrated in Figures 4A-4C, the effect of such polymerization conditions would be to increase the relative rate of reaction (2) more than reaction (1), thereby enhancing the relative rates of reactions (5) and (6) with respect to reactions (3) and (4), particularly in the early stages of the step copolymerization.

[0035] Various embodiments provide copolymer compositions comprising multi-block copolymers. For example, in some embodiments, copolymer compositions are provided comprising multi-block copolymers comprising a first block and a second block. In one embodiment, the first block is substituted with an effective amount of heavy atoms to render it more radiopaque than the second block. In one embodiment, the multi-block copolymer has a number average molecular weight of 100 kDa or greater.

[0036] In some embodiments, the multi-block copolymer is in the form of a single phase. An example of such a single-phase copolymer composition is shown in Figure 3 (discussed in more detail elsewhere herein). The composition of the multi-block copolymer can be selected so that the single phase has a desired glass transition temperature. For example, in one embodiment, a single phase of the multi-block copolymer has a glass transition temperature greater than 37°C.

[0037] In other embodiments, the copolymer composition comprises two or more phases. For example, in one embodiment, the copolymer composition includes a discontinuous first polymer phase and a continuous second polymer phase. The multi-block copolymer composition can be selected such that each phase has a desired glass transition temperature, which may be similar or different from one another. For example, in one embodiment, the discontinuous first polymer phase has a first glass transition temperature greater than 37° C. In one embodiment, the continuous second polymer phase has a second glass transition temperature greater than 37° C. In phase-separated multi-block copolymer embodiments, the discontinuous first polymer phase may be relatively concentrated in the first block of the multi-block copolymer and the continuous second polymer phase may be relatively concentrated in the second block of the multi-block copolymer.

[0038] Copolymer compositions containing two or more phases can have a variety of phase morphologies. For example, in one embodiment, the copolymer composition comprises a discontinuous first polymer phase and a continuous second polymer phase. The discontinuous first polymer phase can be in the form of domains dispersed throughout the continuous second polymer phase. Examples of such phase separated copolymer compositions are shown in Figures 1 and 2 (discussed in more detail elsewhere herein). The size of the dispersed domains can vary over a wide range. In some embodiments, the discontinuous first polymer phase has an average domain size that is less than 15 μm, less than 10 μm, less than 5 μm, or less than 1 μm. In one embodiment, the copolymer composition (a) comprises about 50% by weight of PrD-diI2DAT units and about 50% by weight of EGPLLAD7K units, and (b) is not a multiblock copolymer in which the average domain size of the discontinuous first polymer phase is 15 μm or more.

[0039] The copolymer composition described herein can include various multi-block copolymers. In various embodiments, the first block is substituted with an effective amount of heavy atoms to make it more radiopaque than the second block. For example, in various embodiments, the first block of the multi-block copolymer includes one or more units of the following formula (A1): [ka]

[0040] In formula (A1), A 1 is an organic spacer group containing from 4 to 30 carbon atoms; X 1 is I or Br; Each a2 independently represents at least one X in at least one phenyl ring of the unit of formula (A1). 1 is an integer ranging from 0 to 3, provided that I and / or Br atoms are examples of heavy atoms attached to the first block in an amount effective to render the first block more radiopaque than the second block.

[0041] In formula (A1), A 1 can be a variety of organic spacer groups containing from 4 to 30 carbon atoms. For example, in one embodiment, the unit of formula (A1) is a unit represented by formula (A2) below: [ka]

[0042] In formula (A2), the variable a1 is an integer in the range of 1-12. For example, a1 may be an integer in the range of 2-6. In various embodiments, the unit of formula (A2) is a PrD-diI2DAT carbonate unit represented by the following formula: [ka]

[0043] As described herein, various second blocks can be incorporated into the multi-block copolymer. For example, in one embodiment, the second block of the multi-block copolymer comprises one or more units of formula (B1): [ka]

[0044] In formula (B1), each R 1 are each independently H or C 1-6 For example, in one embodiment, each R 1 are each independently hydrogen or methyl. 1 is an organic spacer group containing 1 to 12 carbon atoms. For example, in one embodiment, B1 is C 1-12 In the formula (B1), m and n each independently represent an integer ranging from about 10 to about 5,000. For example, in one embodiment, m and n are each independently an integer in the range of about 30 to about 1000.

[0045] In an embodiment of the copolymer composition, the unit of formula (B1) is a unit represented by formula (B2): [ka]

[0046] In formula (B2), b1 is an integer ranging from about 1 to about 12. In one embodiment, each R of formula (B1) or (B2) 1 is each independently hydrogen or methyl, and m and n are each independently an integer ranging from about 30 to about 100. In one embodiment of the copolymer composition, the unit of formula (B2) is a unit of formula (B3): [ka]

[0047] In formula (B3), m1 and m2 are integers such that the sum of m1 and m2 is equal to m in formula (B2). Similarly, the variables n1 and n2 in formula (B3) are integers such that the sum of n1 and n2 is equal to n in formula (B2). In one embodiment, the copolymer composition comprises a multi-block copolymer having at least one second block of formula (B1) being an EGPLLAD carbonate unit of the formula: [ka]

[0048] The copolymer compositions described herein can include multi-block copolymers having molecular weights that vary widely. In various embodiments, the multi-block copolymers have a number average molecular weight of 100 kDa or more, about 110 kDa or more, about 200 kDa or less, about 175 kDa or less, or any range between any of the foregoing values. For example, in various embodiments, the multi-block copolymer has a number average molecular weight ranging from about 100 kDa to about 200 kDa.

[0049] The copolymer compositions described herein can be made in a variety of ways by one of ordinary skill in the art using routine experimentation guided by the teachings provided herein, including the following examples and Figures 1-5. For example, in one embodiment, there is provided a method of making the copolymer compositions described herein, comprising copolymerizing an aromatic diol monomer of formula (A1a) and an aliphatic diol monomer of formula (B1a). [ka]

[0050] In formula (A1a), A 1 is an organic spacer group containing 4 to 30 carbon atoms. For example, in one embodiment, A 1 is an organic spacer group represented by the following formula (A2). [ka]

[0051] In formula (A2), a1 is an integer ranging from 1 to 12.

[0052] In formula (A1a), X 1 is I or Br, and as discussed elsewhere herein, I and Br atoms are examples of heavy atoms that may be contained in the aromatic diol monomer of Formula (A1a) in an amount effective to render the first block of the resulting multiblock copolymer more radiopaque than the second block. In formula (A1a), each a2 independently represents at least one X in at least one of the phenyl rings of the monomer of formula (a1). 1 is an integer ranging from 0 to 3, provided that X is attached. In various embodiments, a2 is 1 or 2. In one embodiment, X 1 is I and a2 is 1 or 2.

[0053] In formula (B1a), B 1 is an organic spacer group containing 1 to 12 carbon atoms; each R1 are each independently H or C 1-6 and m and n are each independently an integer ranging from about 10 to about 500. The copolymerization of monomers of formula (A1a) and monomers of formula (B1a) is carried out in the presence of a phosgene source under reaction conditions selected to form a multiblock copolymer. One of ordinary skill in the art will be able to select such reaction conditions by employing routine experimentation guided by the teachings provided herein.

[0054] In various embodiments, the monomer of formula (A1a) is a monomer of formula (A1b): [ka]

[0055] In formula (A1b), a1 is an integer ranging from 1 to 12. For example, in various embodiments, the monomer of formula (A1b) is an aromatic diol monomer of the following formula PrD-diI2DAT: [ka]

[0056] In another embodiment, the monomer of formula (A1b) is an aromatic diol monomer of formula EG-diI2DAT: [ka]

[0057] In various embodiments, the monomer of formula (B1a) is a monomer of formula (B1b): [ka]

[0058] In formula (B1b), b 1is an integer ranging from 1 to 12. For example, in various embodiments, the monomer of formula (B1b) is an aliphatic diol monomer of the formula EGPLLAD: [ka]

[0059] In another embodiment, the monomer of formula (B1b) is an aliphatic diol monomer of the formula EGPLGA diol: [ka]

[0060] wherein the variables m1 and m2 are integers such that the sum of m1 and m2 is equal to m in formula (B1b), and n1 and n2 are integers such that the sum of n1 and n2 is equal to n in formula (B1b).

[0061] The molecular weights of the aromatic diol monomers of formula (A1a) and the aliphatic diol monomers of formula (B1a) can be varied over a wide range and therefore can be selected to achieve desired properties in the resulting multiblock copolymers and / or copolymer compositions described elsewhere herein. For example, in various embodiments, the number average molecular weight of the monomers of formula (B1a) ranges from about 2 kDa to about 35 kDa; from about 3 kDa to about 20 kDa; or from about 4 kDa to about 10 kDa.

[0062] The reaction conditions for polymerization between the aromatic diol monomer of formula (A1a) and the aliphatic diol monomer of formula (B1a) to form a multi-block copolymer can be determined by those skilled in the art using routine experimentation guided by the teachings provided herein. The relative amounts of the aromatic diol monomer of formula (A1a) and the aliphatic diol monomer of formula (B1a) can be varied over a wide range, depending on the respective molecular weights and the desired stoichiometry. For example, in various embodiments, the conditions selected to form the multi-block copolymer are such that the weight ratio of the monomer of formula (A1a) to the monomer of formula (B1a) is in the range of 7:3 to 3:7.

[0063] As discussed elsewhere herein with respect to the polymerization kinetics illustrated in Figures 4A-4C, reaction conditions for copolymerizing comonomers in the presence of a phosgene source to make multi-block copolymers can be selected to favor the incorporation of one monomer with respect to another. In one embodiment, the reaction conditions for producing the multi-block copolymer are selected to increase the rate at which the monomer of formula (B1a) is incorporated into the multi-block copolymer in the presence of a phosgene source compared to the rate at which the monomer of formula (A1b) is incorporated. For example, reaction conditions that increase the rate at which the monomer of formula (B1a) is incorporated into the multi-block copolymer (compared to the rate at which the monomer of formula (A1b) is incorporated) include adding a phosgene source to a mixture comprising a monomer of formula (A1a) and a monomer of formula (B1a) at a rate greater than the rate at which the phosgene source reacts with the monomer of formula (A1a). Including In one embodiment, the phosgene source comprises triphosgene.

[0064] In various embodiments, the copolymer compositions taught herein are biocompatible, biodegradable and / or bioabsorbable. Such copolymer compositions are preferred for many practical applications in view of the manner in which their mechanical properties can be improved as taught herein. Various embodiments of the copolymer compositions taught herein can be used to manufacture a variety of useful articles with valuable physical and chemical properties, including for incorporation into implantable medical devices. Useful articles can be formed by conventional polymer thermoforming techniques such as blow molding, extrusion, and injection molding, where the decomposition temperature of the copolymer exceeds the glass transition temperature and / or crystalline melt temperature, or conventional non-thermoforming techniques such as compression molding, injection molding, solvent casting, spin casting, and wet spinning can be used. A combination of two or more methods may be used. Molded articles prepared from these copolymers are particularly useful as biocompatible, biodegradable and / or bioabsorbable biomaterials for medical implant applications.

[0065] Incorporation of the copolymer composition into an implantable medical device can be accomplished in a variety of ways. For example, in some embodiments, the implantable medical device is a stent formed by a process that includes blowing a copolymer composition that constitutes a multi-block copolymer as described herein to form a generally cylindrical shape, such as a tube, suitable for further processing (e.g., laser cutting) to form a stent. In other embodiments, the copolymer compositions constituting the multi-block copolymers as described herein (optionally including a biologically active compound such as sirolimus or rapamycin) can be incorporated into and / or coated on an implantable medical device or portion thereof. The copolymer compositions can be formulated to include a biologically active compound, e.g., a therapeutic agent such as a drug, thereby enabling the implantable medical device to deliver the drug at or near the in vivo site of implantation.

[0066] In various embodiments, the implantable medical device is a stent. The stent may have many different types of configurations. For example, the stent may be an expandable stent. In another embodiment, the stent may be configured to have the configuration of a sheet-like stent, a braided stent, a self-expanding stent, a braided stent, a deformable stent, or a slide-and-lock stent. The stent fabrication process may further include two-dimensional fabrication methods such as cutting an extruded sheet of the copolymer, for example, via laser cutting, etching, mechanical cutting, or other methods, and assembling the resulting cut sections into a stent, or similar methods of three-dimensional fabrication of a device from a solid form.

[0067] In other embodiments, the copolymer forms a coating on the surface of an implantable device, particularly a stent, made of either the copolymer as described herein or another material, such as a metal. Such a coating may be formed on the stent via techniques such as dipping, spray coating, combinations thereof, etc. Additionally, the stent may be comprised of at least one fiber material, curable material, laminate material, and / or woven material. The medical device may also be a stent graft or a device used for embolization therapy.

[0068] Details of stent products and methods of manufacture in which the polymers described herein may be employed are disclosed in U.S. Patent Publication No. 20060034769, which is incorporated by reference, and is disclosed specifically for the purposes of describing such stent products and methods of manufacture. The stents are preferably made from the radiopaque copolymer compositions described herein, allowing for fluoroscopic positioning of the device.

[0069] The highly beneficial combination of properties associated with preferred embodiments of the copolymer compositions described herein means that such copolymer embodiments are suitable for use in manufacturing a variety of resorbable medical devices other than stents, particularly implantable medical devices that have beneficial radiopacity and biocompatibility and various times of bioabsorption. For example, exemplary embodiments of the copolymers may be used in other medical systems, such as the musculoskeletal or orthopedic systems (e.g., tendons, ligaments, bones, cartilage skeleton, smooth muscles); the nervous system (e.g., spinal cord, brain, eyes, inner ear); the respiratory system (e.g., nasal cavity and paranasal sinuses, trachea, larynx, lungs); the reproductive system (e.g., These include the urinary system (e.g., kidneys, bladder, urethra, ureters); the digestive system (e.g., oral cavity, teeth, salivary glands, pharynx, esophagus, stomach, small intestine, colon), exocrine functions (biliary tract, gallbladder, liver, appendix, rectal tract); the endocrine system (e.g., pancreas / islets, pituitary gland); the endocrine system (e.g., pancreas / islets, pituitary gland, parathyroid gland, thyroid gland, adrenal glands, pineal gland), the hematopoietic system (e.g., blood and bone marrow, lymph nodes, spleen, thymus, lymphatic vessels), and the intestinal system (e.g., skin, hair, nails, sweat glands, sebaceous glands).

[0070] Embodiments of the copolymer compositions described herein can be used to make wound closure devices, hernia repair meshes, gastric lap bands, drug delivery implants, envelopes for implantation of cardiac devices, devices for other cardiovascular applications, stents for non-cardiovascular applications such as biliary stents, esophageal stents, vaginal stents, pulmonary tracheal / Broncus stents, etc.

[0071] Additionally, embodiments of the copolymer compositions described herein are suitable for use in making implantable, radiopaque disks, plugs, and other devices used to track areas of tissue removal, for example, in cancerous tissue removal and organ removal, as well as staples and clips suitable for use in wound closure, attachment of tissue to bone and / or cartilage, hemostasis (homeostasis), ligation (ligation), surgical adhesion prevention, and the like. Embodiments of the copolymer compositions described herein are also suitable for use in making various coatings for medical devices, particularly implantable medical devices. Additionally, in some preferred embodiments, embodiments of the copolymer compositions of the present invention can be advantageously used in the manufacture of various resorbable orthopedic devices, including, for example, radiopaque biodegradable screws (interference screws), radiopaque biodegradable suture anchors, and the like, for use in applications including the correction, prevention, reconstruction, and repair of anterior cruciate ligaments (ACLs), rotator cuffs / rotator cuff cups, and other skeletal deformities.

[0072] Other devices that may be advantageously formed from the copolymer embodiments described herein include devices designed for use in tissue engineering. Examples of suitable resorbable devices include tissue engineering scaffolds and grafts (e.g., vascular grafts, grafts or implants used in nerve regeneration). The copolymer embodiments described herein may also be used to form a variety of devices that are effective for use in closing internal wounds. Non-limiting examples include sutures, clips, staples, barbed or mesh sutures, implantable organ supports, and the like for use in various surgical, cosmetic, and cardiac wound closure applications.

[0073] Various devices useful for dental applications can be preferably formed from the embodiments of the copolymer compositions described herein.For example, devices for guided tissue regeneration, alveolar bone crest replacement devices for denture wearers, and devices for maxillofacial bone regeneration may advantageously have one or more of the desirable properties described herein, such as being radiopaque, so that a surgeon or dentist can confirm the placement and continued function of such implants by simple X-ray photography.

[0074] Preferred embodiments of the copolymer compositions described herein are also useful for the manufacture of radiopaque polymeric embolotherapy products for the temporary and therapeutic restriction or interruption of blood supply to treat tumors and vascular malformations, such as uterine fibroids, tumors (i.e., chemoembolization), hemorrhage (e.g., during trauma accompanied by hemorrhage), and arteriovenous malformations, fistulas, and aneurysms. Details of embolotherapy products and methods of manufacture in which embodiments of the copolymer compositions described herein may be employed are disclosed in U.S. Patent Publication No. 20050106119 A1, the disclosure of which is incorporated by reference and is disclosed specifically for the purposes of describing such products and methods. Embolotherapy treatment methods are local rather than systemic in nature, and products are preferably made from radiopaque embodiments of the copolymer compositions described herein to allow for fluoroscopic monitoring of delivery and treatment.

[0075] The polymers described herein are further useful in the manufacture of a wide variety of therapeutic agent delivery devices. Such devices can be adapted for use with a variety of therapeutic agents, including, for example, pharmaceutical agents (i.e., drugs) and / or biological agents as previously defined, including biomolecules, genetic materials, and engineered biological materials. Any number of transport systems capable of delivering therapeutic agents into the body can be made, including devices for therapeutic agent delivery in the treatment of cancer, intravascular problems, dental problems, obesity, infectious diseases, and the like.

[0076] In addition to the multiblock copolymer, the copolymer composition as described herein may include one or more components depending on the intended use, such as, for example, a therapeutic agent, a plasticizer, a filler, a crystallization nucleating agent, a preservative, a stabilizer, a photoactivator, etc. For example, in one embodiment, a medical device comprising the copolymer composition as described herein further comprises an effective amount of at least one therapeutic agent, such as a pharmaceutical agent, a biological agent, and / or a magnetic resonance enhancing agent. Non-limiting examples of preferred pharmaceutical agents include immunosuppressants, chemotherapeutic agents, nonsteroidal anti-inflammatory agents, steroidal anti-inflammatory agents, and wound healing agents. Therapeutic agents may be co-administered with embodiments of the copolymer composition. In a preferred embodiment, at least a portion of the therapeutic agent is included within the copolymer composition. In another embodiment, at least a portion of the therapeutic agent is included within the copolymer coating on the surface of the medical device.

[0077] Non-limiting examples of preferred immunosuppressants include sirolimus and everolimus. Non-limiting examples of preferred chemotherapeutic agents include taxanes, taxinines, taxol, paclitaxel, dioxorubicin, cisplatin, adriamycin, and bleomycin. Non-limiting examples of preferred non-steroidal anti-inflammatory compounds include aspirin, dexamethasone, ibuprofen, naproxen, and Cox-2 inhibitors (eg, Rofexcoxib, Celecoxib, and Valdecoxib). Non-limiting examples of preferred steroidal anti-inflammatory compounds include dexamethasone, beclomethasone, hydrocortisone, and prednisone. Mixtures containing more than one therapeutic agent may also be used. Non-limiting examples of preferred magnetic resonance enhancing agents include gadolinium salts, such as gadolinium carbonate, gadolinium oxide, gadolinium chloride, and mixtures thereof.

[0078] The amount of additional component present in the medical device is desirably selected to be effective for the intended use. For example, the therapeutic agent is preferably present in the medical device in an amount effective to achieve a desired therapeutic effect in the patient to whom the medical device is administered or implanted. Such amounts can be determined by routine experimentation informed by the guidance provided herein. In certain embodiments, the desired therapeutic effect is a biological response. In embodiments, the therapeutic agent in the medical device is selected to promote at least one biological response, preferably selected from the group including thrombosis, cell adhesion, cell proliferation, attraction of inflammatory cells, deposition of matrix proteins, inhibition of thrombosis, inhibition of cell adhesion, inhibition of cell proliferation, inhibition of inflammatory cells, and inhibition of deposition of matrix proteins. The amount of magnetic resonance enhancing agent in the medical device is desirably an amount effective to facilitate diagnostic radiological imaging, and can be determined by routine experimentation informed by the guidance provided herein.

[0079] The term "pharmaceutical agent" as used herein includes substances that stimulate a specific physiological (metabolic) response, intended for the alleviation, treatment, or prevention of disease. The term "biological agent" as used herein includes any substance that has structural and / or functional activity in a biological system, including, but not limited to, organs, tissues, or cell-based derivatives, cells, viruses, vectors, nucleic acids (animal, plant, microbial, and viral) of any sequence and size, natural and recombinant and synthetic, antibodies, polynucleotides, oligonucleotides, cDNA, oncogenes, proteins, peptides, amino acids, lipoproteins, glycoproteins, lipids, carbohydrates, polysaccharides, lipids, liposomes, or other cellular components or organelles (e.g., receptors and ligands). Additionally, as used herein, the term "biological agent" includes any virus, serum, toxin, antitoxin, vaccine, blood, blood components or derivatives thereof, allergen products, or similar products, or arsphenamine or its derivatives (or any trivalent organic arsenic compound) applied to the prevention, treatment, or cure of disease or injury in humans (pursuant to section 351(a) of the Public Health Service Act, 42 U.S.C. 262(a)). In addition, the term "biologic product" means 1) Includes biologically active peptides, proteins, carbohydrates, vitamins, lipids, or nucleic acids produced and purified by natural or recombinant organisms, antibodies, tissues, or synthetic analogs of such molecules; 2) "Genetic material" as used herein includes nucleic acids (deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), genetic elements, genes, alleles, structural genes, regulatory genes, operator genes, gene complements, genomes, genetic codes, codons, anticodons, messenger RNA (mRNA), transfer RNA (tRNA), ribosomal extrachromosomal genetic elements, plasmagens, plasmids, transposons, genetic mutations, genetic sequences, exons, introns, and 3) "Processed biologics" as used herein may include, for example, cells, tissues, or organs that have been engineered. The therapeutic agent may also include vitamin or mineral substances or other natural ingredients.

[0080] For medical devices implanted in the vasculature, e.g., a stent, the amount of therapeutic agent is desirably sufficient to inhibit restenosis or thrombosis, or to affect some other condition of the stented tissue, e.g., to heal vulnerable plaque and / or prevent rupture, or stimulate endothelialization. The therapeutic agent may, according to preferred embodiments, be selected from the group consisting of anti-proliferative agents, anti-inflammatory agents, anti-matrix metalloproteinase agents, and lipid-lowering, cholesterol-modifying agents, anti-thrombotic agents and anti-platelet agents. In some preferred embodiments of the stents, the therapeutic agent is contained within the stent such that the agent is blended with the polymer or mixed by other means known to those skilled in the art. In another preferred embodiment of the stent, the therapeutic agent is delivered from a copolymer coating on the stent surface. In another preferred variation, the therapeutic agent is delivered without a copolymer coating. In other preferred embodiments of the stent, the therapeutic agent is delivered from at least one region or one surface of the stent. The therapeutic agent may be chemically bound to an embodiment of the copolymer or carrier used for delivery of the therapeutic agent to at least a portion of the stent, and / or the therapeutic agent may be chemically bound to an embodiment of the copolymer that comprises at least a portion of the stent body. In one preferred embodiment, multiple therapeutic agents can be delivered. Density of copolymer materials with different degrees of phase separation

[0081] The degree of phase separation in exemplary embodiments of the multi-block copolymers as described herein varies depending on the degree of phase separation. Examples of copolymers having less discrete phase separation (eg, a continuous phase) have substantially higher densities than examples having more phase separation (eg, larger discrete domains). Thus, the degree of phase separation affects the overall density of the copolymer material.

[0082] The effect of phase separation on density is shown in Table 1 in Figure 5, which shows examples of absolute (skeletal) densities of blown or "blown" tubes formed from three multiblock copolymers with the same overall composition (Poly(50%PrD-diI2DAT-co-50%EGPLLAD7k) carbonate) but different degrees of phase separation. These density values ​​are shown in Table 1 along with SEM images of the corresponding copolymers. Skeletal density was measured by the Micromeritics gas pycnometer method. Mechanical properties of materials with different degrees of phase separation

[0083] The degree of phase separation in multi-block copolymers as described herein can have a substantial impact on the mechanical properties of the material.

[0084] Testing of copolymer film samples The tensile properties of films prepared from poly(50%PrD-diI2DAT-co-50%EGPLLAD7k) carbonate multiblock copolymers with different degrees of phase separation were measured and are shown in Table 2. Testing was performed under physiologically relevant conditions (37° C. in water) using rectangular strips with an Instron tensile tester at a deformation rate of 10 inches / minute. Films of similar thickness were prepared by compression molding the corresponding copolymer powders at 190°C.

[0085] The data in Table 2 show that (a) there is a tendency for load-bearing parameters such as yield stress and modulus to increase, and (b) there is a very large increase in elongation at break as the size of the discontinuous phase in the multiblock copolymer decreases. This indicates that the toughness of the multi-block copolymer material increases with decreasing size of the discrete phase. [Table 2]

[0086] Testing of blown and extruded copolymer tubing samples The tensile properties of extruded / blow molded tubes of Poly(50%PrD-diI2DAT-co-50%EGPLLAD7k) carbonate multiblock copolymer with different degrees of phase separation were also measured and are shown in Table 3. Rectangular copolymer strips were cut from 3.5 mm inner diameter blown tubes and tested at room temperature (22 °C) in air and physiologically relevant conditions (37 °C in water) using an Instron tensile tester at a deformation rate of 10 in / min. The data in Table 3 show that load-bearing properties such as strength and modulus increase as the size of the discontinuous phase decreases. The elongation at break also tends to increase as the size of the discontinuous phase decreases, and this, combined with the increased load-bearing properties, significantly improves the toughness of the material. The difference in elongation at break between multiblock copolymers with different phase separations is particularly evident when tested under non-plasticized conditions (e.g., in air at 22°C). [Table 3] Radiation capacity of materials with different degrees of phase separation

[0087] The degree of phase separation in multi-block copolymers as described herein having distinct phases with radiopaque properties can have a substantial effect on the overall radiopacity of the material. Scaffolds with similar thickness (approximately 125 μm) were fabricated from poly(50%PrD-diI2DAT-co-50%EGPLLAD7k) carbonate multiblock copolymers with different degrees of phase separation, and their radiopacity was measured using a FeinFocus FXS 100.24 digital X-ray system with custom software developed by CPG on the LabVIEW platform (X-ray Analysis, v.1.0.1). Radiopacity was assessed by qualitatively determining the specific difference in pixel intensity between images of the test sample and images of standard aluminum process wedges (Alloy 110, 3 mm and 0.5 mm process) according to ASTM F640-12. Scaffolds from multiblock copolymers with discrete phase sizes less than 5 μm had equivalent alloy thickness parameter values ​​in the range of 0.70–0.81 mm, whereas scaffolds of similar thickness made from the same chemical composition copolymers but with discrete phase sizes in the range of 10–15 μm had equivalent alloy thickness parameter values ​​approximately 50% lower. Polymer Preparation Examples Comparative Example 1 PrD-diI, as described in Example 21 of U.S. Pat. No. 9,416,090 2 Preparation of multiblock copolymers containing DAT carbonate units and EGPLLAD7K carbonate units

[0088] A 1 L 3-neck round bottom flask equipped with a mechanical stirrer and liquid addition apparatus was charged with 30 g (0.034 mol) of PrD-diI2DAT, 30 g (0.004 mol) of EGPLLAD7K (having a number average molecular weight of approximately 7 kDa), 11.4 g (0.145 mol) of pyridine, and 360 mL of chloroform and stirred for 15 min to obtain a clear solution (the solution was slightly cloudy). Triphosgene (3.96 g, 0.04 mol of phosgene) was dissolved in 12 mL of chloroform and this solution was introduced into the reaction flask over 2-3 h. After the addition was complete, the reaction mixture was quenched with a mixture of 135 mL of THF and 15 mL of water. 350 mL of water was added to the reaction mixture and stirred for 5 min. After the layers were allowed to separate, the top aqueous layer was removed and discarded. The wash was repeated by adding two more 350 mL of DI water. The reaction mixture was then precipitated with 700 mL of IPA. The resulting gel was triturated twice with 550 mL of IPA in a 4 L blender. The product was isolated by filtration and dried in a vacuum oven at 80 °C. The resulting 50% EGPLLAD polymer was compression molded at 190 °C to give a uniform, transparent film.

[0089] The copolymer thus obtained had a number average molecular weight of about 75 kDa and two glass transition temperatures, about 62°C and about 120°C. Example 2 PrD-diI 2 Preparation of multiblock copolymers containing DAT carbonate units and EGPLLAD7K units with relatively small phase-separated domains

[0090] The reaction was carried out in a 12 L jacketed cylindrical vessel with a removable lid. The lid was equipped with a dynamic viscometer, nitrogen inlet and outlet, pump inlet for triphosgene solution addition, and a stirrer paddle. To the vessel, 600±3 g of PrD-diI2DAT and 600±3 g of EGPLLAD7K (having a number average molecular weight of about 7 kDa) were added. The mixture was dried at 45° C. for 72 hours. After 72 hours of drying, the temperature was reduced to 22° C. and 9600±3 g of chloroform and 251±3 g of pyridine were added to the vessel. The contents were stirred until the solids went into solution. A triphosgene solution was prepared by stirring 87.7 g of triphosgene in 250.7 g of chloroform. The triphosgene solution was added to the vessel over 4 hours at a rate of 1.18 ml / min and the reaction mixture was stirred at 22° C. for about 16 hours, after which the temperature was increased to 30° C. and stirred for 30 minutes. The reaction mixture was quenched by the addition of a mixture of 900 mL of THF and 100 mL of water.

[0091] The product was isolated as a granular powder from the reaction mixture by precipitation with 2-propanol (IPA). The product was dried in a vacuum oven at 45° C. The product was further dried at 100° C. prior to thermal processing.

[0092] The copolymer thus obtained had a number average molecular weight of about 135 kDa and two glass transition temperatures, about 62°C and about 120°C. Example 3 Carbonate PrD-diI 2 Preparation of multiblock copolymers containing DAT carbonate units and EGPLLAD7K carbonate units with no phase-separated domains visible by SEM

[0093] The reaction was carried out in a 12 L jacketed cylindrical vessel with a removable lid. The lid was equipped with nitrogen inlet and outlet, a pump inlet for the addition of triphosgene solution, and an overhead stirrer paddle. To the vessel, 600±3 g of PrD-diI2DAT and 600±3 g of EGPLLAD7K (having a number average molecular weight of about 7 kDa) were added. The mixture was dried at 45° C. for 72 hours. After 72 hours of drying, the temperature was reduced to 22° C. and 9600±3 g of chloroform and 251±3 g of pyridine were added to the vessel. The contents were stirred until the solids went into solution. A triphosgene solution was prepared by stirring 87.7 g of triphosgene in 250.7 g of chloroform. The triphosgene solution was pumped into the vessel at a rate of 2.15 ml / min over a period of about 2 hours and stirred for about 1.5 hours, after which the temperature was increased to 30° C. and stirred for 30 minutes. The reaction mixture was quenched by the addition of a mixture of 900 mL of THF and 100 mL of water.

[0094] The product was isolated in the form of a granular powder from the reaction mixture by multiple precipitation with 2-propanol (IPA). The product was dried in a vacuum oven at 45° C. The product was further dried at 100° C. prior to thermal processing.

[0095] The resulting copolymer had a number average molecular weight of about 135 kDa and a glass transition temperature of about 62°C. Example 4 EG-diI 2 Preparation of multiblock copolymers containing DAT carbonate units and EGPLLAD7K carbonate units

[0096] 50 g (0.058 mol) of EG-diI2DAT, 50 g (0.0071 mol) of EGLLAD7K (having a number average molecular weight of about 7 kDa), 11.4 g (0.276 mol) of pyridine and 540 mL of chloroform were placed in a 1 L three-necked round bottom flask equipped with a mechanical stirrer and liquid addition apparatus and stirred for 15 min to obtain a clear solution. Triphosgene (8.73 g, 0.084 mol of phosgene) was dissolved in 31 ml of chloroform and this solution was introduced into the reaction flask over 3 h. The reaction mixture was transferred to a 2 L beaker. 750 mL of IPA was slowly added to the reaction mixture while stirring. The polymer precipitated as a gel. The gel was transferred to a 4 L industrial blender and ground with 750 mL of IPA. The polymer was obtained as fine particles. It was dried in a vacuum oven at 55 °C for 24 h and at 100 °C for 1 h. To remove the last traces of pyridine, the polymer was dissolved in 600 mL of dichloromethane (DCM) in a 2 L beaker and 900 mL of IPA was added at a slow rate to the resulting viscous solution. The product precipitated as fine particles. After removing the supernatant, the precipitate was stirred with 300 mL of IPA. After removing the supernatant, the last step was repeated two more times. The precipitate was finally isolated by filtration and dried in a vacuum oven at 55 °C for 90 h. Example 5 EG-diI 2 Preparation of multiblock copolymers containing DAT carbonate units and EGPLLAD15K carbonate units.

[0097] In a 2 L 3-neck round bottom flask equipped with a mechanical stirrer and liquid addition apparatus, 50 g (0.058 mol) of EG-diI2DAT, 50 g (0.0033 mol) of EGLLAD15K (number average molecular weight approximately 15 kDa), 22.24 mL (0.276 mol) of pyridine, and 540 mL of chloroform were placed and stirred for 15 minutes to obtain a clear solution. Triphosgene (8.73 g, 0.084 mol of phosgene) was dissolved in 31 mL of chloroform, and this solution was introduced into the reaction flask over 3 hours. The reaction mixture was transferred to a 2 L beaker. With stirring, 900 mL of IPA was slowly added to the reaction mixture. The polymer precipitated as a fine powder and was isolated by filtration. The precipitate was returned to the flask, 300 mL of IPA was added, stirred, and then isolated by filtration. The precipitate was dissolved in 500 mL of DCM when a slightly opaque solution was obtained. 750 mL of IPA was added to precipitate the polymer. The supernatant was removed, the precipitate was stirred with 400 mL of IPA, and the polymer was isolated by filtration and washed on the filter with 250 mL of IPA. The polymer was dried in a vacuum oven at 55° C. for 100 hours. Example 6 Preparation of poly(lactide-co-glycolide) diol with molecular weight of 3000 (EGPLGA3000 diol)

[0098] In a 1 L 3-neck round bottom flask, 100 g of L-lactide and 100 g of glycolide were placed. The monomer mixture was stirred under nitrogen using a stainless steel stirrer. The flask was heated to a temperature of 50 °C in an oil bath for 2 hours with nitrogen flow. The temperature was increased to 110 °C and 4.23 g of ethylene glycol was added using a syringe. The temperature was increased to 150 °C, 40.12 g of Zr(acac) was added, and stirring was continued for 5 hours, after which it was cooled to room temperature. 500 mL of chloroform was added to the solids and stirred for 24 hours, after which most of the solids were dissolved and some gel particles were also present. A clear solution was separated and the product was precipitated by adding heptane to this solution. The solid product was separated and dried in a vacuum oven at 45 °C for 3 days.

[0099] The product was further purified by stirring with 500 mL of acetone and separating the precipitate using a centrifuge. The solid product (EGPLGA3000 diol) was dried in a vacuum oven at 40°C. Example 7 Poly(50% PrD-diI 2 Preparation of DAT-co-50% PLGA3000 (carbonate)

[0100] A 1 L 3-neck round bottom flask equipped with a mechanical stirrer and liquid addition apparatus was charged with 72 g of PrD-diI2DAT, 72 g of EGPLGA3000 diol (prepared as described in Example 6), 34.7 g of pyridine, and 1150 mL of chloroform and stirred for 15 min to obtain a clear solution. Triphosgene (12.09 g, 0.122 mol of phosgene) was dissolved in 31 mL of chloroform and this solution was introduced into the reaction flask over 3.5 h. The reaction mixture was quenched by adding 120 mL of 10% THF in water. 1.5 L of IPA was slowly added to the reaction mixture with stirring and allowed to settle. The supernatant was siphoned out and the precipitate was further treated with (i) 800 mL of IPA, (ii) 400 mL of IPA.

[0101] The precipitate was redissolved in 850 mL of dichloromethane (DCM) and precipitated with IPA (1.5 L), followed by treatment with IPA as above. This step was repeated once more, and the product was transferred to a 4 L industrial blender and triturated with 750 mL of IPA. Finally, the product was dissolved in 700 mL of DCM. This was precipitated with 1500 mL of IPA, and the polymer was isolated by centrifugation at 3000 rpm for 10 min. The top layer was removed, and the polymer was washed three times with 200 mL each of IPA, followed by centrifugation at 300 rpm for 10 min. The product was transferred to a glass pan and dried in a vacuum oven at 55 °C for 24 h to obtain poly(50%PrD-diI2DAT-co-50%PLGA3000 carbonate), a multiblock copolymer containing 50% units of PrD-diI2DAT carbonate and 50% units of EGPLGA30000 carbonate. Example 8 PrD-diI 2 Preparation of multiblock copolymers containing DAT carbonate units and EGPLLAD14K carbonate units

[0102] A 3 L 3-neck flask equipped with a mechanical stirrer and liquid addition apparatus was charged with 75 g of PrD-diI2DAT, 75 g of EGPLLAD14K, 29.68 g of pyridine, and 1200 mL of chloroform and stirred for 15 min to obtain a clear solution. Triphosgene (10.39 g, 0.122 mol of phosgene) was dissolved in 41 mL of chloroform and this solution was introduced into the reaction flask over 2 h. The reaction mixture was stirred overnight and then quenched by adding 120 mL of 10% THF in water. With stirring, 800 mL of IPA was slowly added to the reaction mixture and allowed to settle. The supernatant was siphoned out and the precipitate was further treated with (i) 800 mL of IPA and (ii) 400 mL of IPA. The precipitate underwent multiple redissolutions and reprecipitations in DCM to remove impurities. The product was transferred to a drying pan and dried in a vacuum oven at 100° C. for 24 hours to obtain a multiblock copolymer containing PrD-diI2DAT carbonate units and EGPLLAD14K carbonate units. Example 9 Tetraethylene glycol-diI 2 DAT(TEG-diI 2 Preparation of multiblock copolymers containing EGLLAD7K carbonate units and DAT carbonate units

[0103] A 3 L 3-neck flask equipped with a mechanical stirrer and liquid addition apparatus was charged with 100 g of monomers TEG-di I2DAT, 100 g of PLLAD7K, 39.91 mL of pyridine, and 1081 mL of chloroform, and stirred for 15 min to obtain a clear solution. Triphosgene (13.07 g) was dissolved in 35 mL of chloroform and introduced into the reaction flask until a viscous solution was obtained. The reaction mixture was stirred overnight and then quenched by adding 190 mL of 10% THF in water. 1500 mL of IPA was added to the reaction mixture while stirring and allowed to stand overnight. The supernatant was siphoned out and the precipitate was treated with a further 750 mL of IPA and 350 mL of IPA, removing the supernatant after each treatment. The precipitate was separated using a Büchner funnel under vacuum. The product was dried in a vacuum oven at 45° C. for 48 hours to obtain a multiblock copolymer containing TEG-diI2DAT carbonate units and EGPLLAD7K carbonate units.

Claims

1. A copolymer composition comprising a multi-block copolymer including a first block and a second block, the first block is substituted with heavy atoms in an amount effective to render it more radiopaque than the second block, and the multi-block copolymer has a number average molecular weight of 100 kDa or greater; the multi-block copolymer is in single-phase form at 500x magnification and has a single-phase glass transition temperature greater than 37°C; The first block of the multi-block copolymer comprises one or more units of the following formula (A1): [Case 1] The second block of the multi-block copolymer comprises one or more units of formula (B1): [Case 1A] The multi-block copolymer is a copolymer reaction product of an aromatic diol monomer represented by the following formula (A1a) and an aliphatic diol monomer represented by the following formula (B1a): [chemical 1B] In the formula, A １ is an organic spacer group containing 4 to 30 carbon atoms; B １ is an organic spacer group containing 1 to 12 carbon atoms; Each R １ are each independently H or C １－６ is an alkyl group of X １ is I or Br, Each a2 independently represents at least one X in at least one phenyl ring of the unit of formula (A1a). １ is an integer ranging from 0 to 3, provided that m and n are each independently an integer ranging from 10 to 500; The copolymerization of the monomer of formula (A1a) with the monomer of formula (B1a) is carried out in the presence of a triphosgene source, the triphosgene source is added to the mixture comprising the monomer of formula (A1a) and the monomer of formula (B1a) at a rate greater than the rate at which it reacts with the monomer of formula (A1a); The reaction conditions selected to form the multi-block copolymer include reaction conditions that increase the rate at which the monomer of Formula (B1a) is incorporated into the multi-block copolymer compared to the rate at which the monomer of Formula (A1a) is incorporated. Copolymer compositions.

2. The copolymer composition according to claim 1, wherein the unit represented by formula (A1) is a unit represented by the following formula (A2): [chemical 2] In the formula, a1 is an integer ranging from 1 to 12.

3. The copolymer composition of claim 2, wherein a1 is an integer ranging from 2 to 6.

4. The unit of the formula (A2) is PrD-diI represented by the following formula: ２ 3. The copolymer composition of claim 2, wherein the unit is a DAT carbonate unit. [C3]

5. The copolymer composition according to any one of claims 1 to 4, wherein the unit of formula (B1) is a unit represented by the following formula (B2): [C5] In the formula, b1 is an integer ranging from 1 to 12.

6. Each R １ The copolymer composition of any one of claims 1 to 5, wherein is independently hydrogen or methyl, and m and n are each independently an integer in the range of 30 to 100.

7. The copolymer composition according to claim 6, wherein the unit of formula (B2) is a unit represented by the following formula (B3): [C6] wherein m1 and m2 are integers such that the sum of m1 and m2 is m; n1 and n2 are integers such that the sum of n1 and n2 is n.

8. The copolymer composition according to any one of claims 1 to 7, wherein the unit of formula (B1) is an EGPLLAD carbonate unit of the following formula: [C7]

9. A method for producing the copolymer composition according to any one of claims 1 to 8, comprising the steps of: The method includes copolymerizing an aromatic diol monomer represented by the following formula (A1a) with an aliphatic diol monomer represented by the following formula (B1a), [C8] In the formula, A １ is an organic spacer group containing 4 to 30 carbon atoms; B １ is an organic spacer group containing 1 to 12 carbon atoms; Each R １ are each independently H or C １－６ is an alkyl group of X １ is I or Br, Each a2 independently represents at least one X in at least one phenyl ring of the unit of formula (A1a). １ is an integer ranging from 0 to 3, provided that m and n are each independently an integer ranging from 10 to 500; the copolymerization of the monomer of formula (A1a) with the monomer of formula (B1a) is carried out in the presence of a phosgene source under reaction conditions selected to form a multi-block copolymer; the reaction conditions selected to form the multi-block copolymer include reaction conditions that increase the rate at which the monomer of Formula (B1a) is incorporated into the multi-block copolymer compared to the rate at which the monomer of Formula (A1a) is incorporated; 13. The method of claim 12, wherein the reaction conditions for increasing the rate at which the monomer of Formula (B1a) is incorporated into the multi-block copolymer comprise adding a phosgene source to a mixture comprising the monomer of Formula (A1a) and the monomer of Formula (B1a) at a rate greater than the rate at which the monomer of Formula (A1a) is reacted.

10. A １ is represented by the following formula (A ２ The method according to claim 9, wherein the organic spacer group is represented by the formula: [C9] In the formula, a1 is an integer ranging from 1 to 12.

11. X １ The method of claim 9 or 10, wherein a2 is 1 or 2.

12. The method according to any one of claims 9 to 11, wherein the monomer of formula (A1a) is a monomer represented by the following formula (A1b): [C10] In the formula, a1 is an integer ranging from 1 to 12.

13. The monomer of formula (A1b) is PrD-diI of the following formula: ２ 13. The method of claim 12, wherein the aromatic diol monomer of DAT is an aromatic diol monomer. [C11]

14. The monomer of formula (A1b) is EG-diI of the following formula: ２ 13. The method of claim 12, wherein the aromatic diol monomer of DAT is an aromatic diol monomer. [C12]

15. The method according to any one of claims 9 to 14, wherein the monomer of formula (B1a) is a monomer represented by the following formula (B1b): [C13] In the formula, b1 is an integer ranging from 1 to 12.

16. 16. The method of claim 15, wherein the monomer of formula (B1b) is an aliphatic diol monomer of formula EGPLLAD: [C14]

17. 16. The method of claim 15, wherein the monomer of formula (B1b) is an aliphatic diol monomer of the formula EGPLGA diol: [C15] wherein m1 and m2 are integers such that the sum of m1 and m2 is m; n1 and n2 are integers such that the sum of n1 and n2 is n.

18. 18. The method according to any one of claims 9 to 17, wherein the number average molecular weight of the monomer of formula (B1a) is in the range of 2 kDa to 35 kDa.

19. 19. The method of claim 18, wherein the number average molecular weight of the monomer of formula (B1a) is in the range of 3 kDa to 20 kDa.

20. 20. The method of claim 19, wherein the number average molecular weight of the monomer of formula (B1a) is in the range of 4 kDa to 10 kDa.

21. 21. The method of any one of claims 9 to 20, wherein the conditions selected to form the multi-block copolymer are such that the weight ratio of the monomer of formula (A1a) to the monomer of formula (B1a) is in the range of 7:3 to 3:

7.

22. 22. The process of any one of claims 9 to 21, wherein the phosgene source comprises triphosgene.

23. An implantable medical device comprising the copolymer composition of any one of claims 1 to 8.

24. 24. The implantable medical device of claim 23, further comprising a biologically active compound.

25. 25. The implantable medical device of claim 23 or 24, in the form of a stent.

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