Absorbent copolymer with improved thermal stability

Abstract

To provide absorbable block copolymers with improved characteristics including thermal stability, molecular weight consistency, and inherent viscosity retention following melt extrusion, and uses thereof.SOLUTION: A polymer includes a polyaxial core, with at least three axes, and a pre-polymer. The at least three axes comprise polymeric chains. There is also at least one flexible linking segment. Further, at least one polymeric end graft is attached to each of the at least three axes, and comprises repeat units derived from at least one cyclic monomer capable of crystallization.SELECTED DRAWING: Figure 6A

Description

Technical Field

[0001] The present invention relates to an absorbent copolymer having improved properties including thermal stability, molecular weight consistency, and intrinsic viscosity retention after melt extrusion, and a method for producing the improved absorbent copolymer. The present invention further relates to an absorbent fibrous construct that can be used for controlled drug delivery.

Background Art

[0002] Previous research in the polymer field, such as U.S. Patent No. 6,462,169 to Shalaby, discloses a multiaxial block polyester containing high glycolide end grafts. However, the polymers obtained from this disclosure lack various properties as compared to the present disclosure, such as thermal stability, molecular weight consistency, and intrinsic viscosity retention after melt extrusion. Further, the fibers produced from the disclosure of No. 169 lack the strength and toughness exhibited by the fibers produced from the polymers of the present disclosure. Further, the polymers disclosed in No. 169 are limited to a multiaxial block structure synthesized in a solid state at 180°C. The polymers of the disclosure of No. 169 are synthesized in two steps that require first synthesizing a prepolymer and then end-grafting to obtain a crystallizable end segment. The end segment is synthesized by reacting the prepolymer with monomers at 180°C until the reaction content becomes solid, and then continuing the reaction in the solid state at the same temperature for more than 2 hours.

[0003] Furthermore, Shalaby's U.S. Patent No. 6,498,229 discloses high-glycolide block copolymers synthesized in solid state. The polymers disclosed in No. 229 are not limited to just one example and are synthesized with a larger amount of catalyst than those used to synthesize the high-glycolide polymers described herein. Specifically, the polymers in No. 229 are synthesized with a monomer-to-catalyst (M / C) ratio of 60,000. The polymers obtained from the disclosure of No. 229 are not only formed from solid-state synthesis using more catalyst, but also lack thermal stability, molecular weight consistency, and the retention of intrinsic viscosity after melt extrusion of polymers produced according to this disclosure. Furthermore, the references in No. 229 are limited to polymer compositions synthesized by a single-step reaction. The polymers also contain less than 80 mol% (and more than 20 mol%) of glycolide-derived repeating units. Moreover, the two-step synthesis method in No. 229 may have "considerably poor reproducibility." However, unexpectedly, in contrast to the disclosure in No. 229, the polymers in this disclosure exhibit more than adequate reproducibility despite being synthesized by a two-step method. Furthermore, Shalaby's U.S. Patent No. 6,342,065 discloses a high lactide block copolymer synthesized in a solid state by a two-step process. However, the polymer obtained from the disclosure of No. 065 lacks thermal stability, molecular weight consistency, retention of intrinsic viscosity after melt extrusion, and the improved fiber strength of the polymer described herein. Furthermore, Zhao, U.S. Patent No. 7,265,186, discloses multiaxial structures having hydrophilic cores as star-shaped block copolymers. These cores are not hydrolyzable.

[0004] On the other hand, U.S. Patent No. 8,262,723 discloses an implantable medical device made from a branched / multiaxial polymer. While Wang describes branched / multiaxial constructs, the multiaxial block always exists with a second, different polymer having the same chemical structure as the end block of the multiaxial block. This disclosure provides discontinuous phases that do not constitute a blend of a second phase containing a multiaxial end block with a second polymer and a prepolymer. The novel compositions disclosed herein form different discontinuous phases formed from blocks of end grafts and / or blocks of prepolymers. In this disclosure, if the multiaxial may exist in combination with a second polymer having the same or similar composition as the multiaxial end block, the chain length and degree of polymerization of the second polymer are twice that of the multiaxial end block. Furthermore, Wang does not disclose flexible linking segments as disclosed herein. Jakubowski, U.S. Patent No. 8,569,421, describes multiaxial polymers having multiple axes. However, these compositions are not symmetrical and are intentionally designed to have unsaturated bonds distributed at specific positions along the polymer arms, making the polymer more oxidatively stable. Jakubowski constructs are not intended to be biodegradable / absorbable. Furthermore, they do not specifically relate to implantable compositions. Himes, U.S. Patent No. 5,639,831, relates to multiaxial block copolymers for applications different from those described herein. Furthermore, these copolymers do not require the same chemical functionality and biocompatibility as the polymers described herein. Therefore, the object of the present invention is to provide an absorbent copolymer having thermal stability, improved molecular weight consistency, and higher intrinsic viscosity retention after melt extrusion, the fibers produced from the copolymer exhibit increased strength. [Overview of the project]

[0005] The above objective is achieved, according to the present invention, in a first embodiment, by preparing an absorbent aliphatic polyester copolymer. The copolymer comprises a multiaxial core having at least three axes and a prepolymer. At least three axes contain polymer chains. There is also at least one flexible bond segment. Furthermore, at least one polymer end graft is attached to each of the at least three axes, and the end graft contains repeating units derived from at least one crystalline cyclic monomer. In a further embodiment, the multiaxial core includes crystallizable polymer chain segments. Alternatively, the multiaxial core includes amorphous chain segments. In another embodiment, the flexible bond segment and the crystallizable cyclic monomer share a common monomer. In yet another embodiment, the flexible bond segment is composed of the same prepolymer as the multiaxial core and the same crystallizable cyclic monomer as at least one polymer end graft.

[0006] Furthermore, the prepolymer may be a homopolymer, copolymer, or terpolymer formed from the group consisting of L,L-lactide, D,L-lactide, glycolide, substituted glycolide, paradioxanone, 1,5-dioxepant-2-one, trimethylene carbonate, epsilon-caprolactone, alpha-angelicalactone, gamma-valerolactone, delta-valerolactone, or combinations thereof. Furthermore, the prepolymer may be derived from ε-caprolactone, trimethylene carbonate, or a combination of the two thereof. Furthermore, the prepolymer may be derived from glycolide, trimethylene carbonate, or a combination of the two thereof. In a further embodiment, the copolymer comprises at least four distinct blocks, including a central crystallizable core having at least three axes, which contains crystallizable terminal blocks grafted in at least three axes. Furthermore, at least one crystallizable cyclic monomer may be selected from the group consisting of L,L-lactide, D,L-lactide, glycolide, substituted glycolide, paradioxanone, 1,5-dioxepant-2-one, trimethylene carbonate, epsilon-caprolactone, alpha-angelicalactone, gamma-valerolactone, delta-valerolactone, or combinations thereof. In another embodiment, the flexible bond segment may be derived from trimethylene carbonate, ε-caprolactone, or a combination of two thereof. Furthermore, the polyester copolymer may also comprise absorbent barriers, webs, meshes, or fabrics. Moreover, the copolymer may be formed into a warp-knit mesh. Furthermore, the copolymer may also comprise an absorbent polymer surface coating for controlled drug delivery.

[0007] In another embodiment, a method for producing an absorbent aliphatic polyester copolymer is provided. The method includes the step of filling a reactor with monomers, an initiator, and a catalyst, wherein the monomer-to-catalyst ratio is at least 25,000. The initiator may have at least one hydroxyl group capable of initiating ring-opening polymerization. The monomers may include at least one cyclic monomer. The reactor is heated to at least 100°C. The monomers may be stirred to form a homogeneous mixture prepolymer, the mass of which is greater than 10 kDa. A copolymer having a plurality of amorphous prepolymer axes and crystalline end grafts extending from each axis may then be formed.

[0008] In further embodiments, the catalyst may be a first tin octoate. Other catalysts include Sn(Oct)2, Sn(OTf)2, dibutyltin(II)-2-ethylhexanoate (Bu2Sn(Oct)2), and 4-(dimethylamino)pyridine (DMAP). Furthermore, the initiator may be selected from the group consisting of hydroxyl-containing small molecules, oligomers, polymers, inorganic salts, organic salts, or combinations thereof. Furthermore, the initiator may be selected from the group consisting of 1-decanol, 1,3-propanediol, trimethylolpropane, triethanolamine, 1,3,4-trihydroxy-2-butanone, glycerol, or combinations thereof. In further embodiments, the monomer may be a copolymer or terpolymer derived from lactide, trimethylene carbonate, and / or ε-caprolactone. In further embodiments, the monomer may be a copolymer or terpolymer derived from glycolides, trimethylene carbonates, and / or ε-caprolactone. In another embodiment, the monomer may be a substituted glycolide. In further embodiments, a second packing of the catalyst may be added to the reactor. In further embodiments, two independent temperature settings may be established during the reaction. The following describes a configuration designed to carry out the present invention, along with other features of the present invention. The present invention will be more readily understood by reading the following description, which illustrates an example of the present invention, and by the accompanying drawings, which form part thereof. [Brief explanation of the drawing]

[0009] [Figure 1] This graph shows the thermogravimetric analysis (TGA) results of the polymer of the present invention. [Figure 2] This figure shows one embodiment of the contents of this disclosure in the form of a warp-knit 3-bar structure. [Figure 3] This figure shows one embodiment of the contents of this disclosure in the form of a tricot warp knit 2-bar structure. [Figure 4] This figure shows one embodiment of the disclosed material in the form of a warp-knitted 2-bar "sharkskin" structure. [Figure 5] This figure shows another embodiment of the contents of this disclosure in the form of a half-tricot pattern. [Figure 6A] This figure shows a fully extended chain depiction of a semicrystalline multiaxial block copolymer. [Figure 6B] This figure shows an amorphous multiaxial core with polymer amorphous arms having crystallizable end grafts. [Figure 7A] This figure shows a multiaxial block copolymer without flexible linkers connecting the prepolymer to the terminal grafts. [Figure 7B] This figure shows polymer structures using flexible linker prepolymers and terminal grafts. [Figure 8] This formula shows the remaining prepolymer after mixing and reacting a second charge containing a prepolymer at a high catalyst concentration. [Figure 9] This data shows incomplete mixing / heterogeneity based on GPC analysis. [Figure 10] Figure 8 shows the data illustrating the analysis of the polymer. [Figure 11] This figure shows the polymer described in this disclosure. [Figure 12] This figure shows another embodiment of a multiaxial block copolymer containing multiple segments. [Figure 13] This figure shows a four-arm multiaxial copolymer with directional orientation along the axis. [Figure 14] Figure 13 is an excerpt showing an exemplary polymer chain folding of arms that results in a folded crystal. [Figure 15] This figure shows an asymmetric multiaxial copolymer. [Figure 16] This is a diagram showing a superbranched microstructure polymer.

[0010] Those skilled in the art will understand that one or more embodiments of the present invention may satisfy certain purposes, while one or more other embodiments may satisfy certain other purposes. Each purpose may not be equally applicable to all embodiments of the present invention in all respects. Thus, the above-mentioned subjects can be seen as substitutes with respect to any embodiment of the present invention. These and other subjects and features of the present invention will become more fully apparent when the following detailed description is read in conjunction with the accompanying drawings and examples. However, it should be understood that both the above summary and the following detailed description of the present invention are preferred embodiments and do not limit the present invention or other alternative embodiments of the present invention. In particular, while the present invention is described herein in terms of many specific embodiments, it should be understood that the descriptions are illustrative of the present invention and are not intended to limit the present invention. As described by the appended claims, various modifications and applications will be possible for those skilled in the art without departing from the spirit and scope of the present invention. Similarly, other subjects, features, advantages and effects of the present invention will become apparent from this summary and certain embodiments described below and will be readily apparent to those skilled in the art. Such objects, features, advantages, and effects will become apparent from the above, along with the attached examples, data, drawings, and all reasonable inferences derived therefrom, as well as from the references, either alone or incorporated herein. [Modes for carrying out the invention]

[0011] Herein, the present invention will be described in further detail with respect to the drawings. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the subject matter disclosed herein belongs. Any methods, devices, and materials similar to or equivalent to those described herein may also be used in carrying out or testing the subject matter disclosed herein, but representative methods, devices, and materials are described herein. The present disclosure relates to an absorbent aliphatic polyester having improved properties including thermal stability, molecular weight consistency, and intrinsic viscosity retention after melt extrusion. Further, fibers made from the polymer will have increased strength. In one embodiment, the aliphatic polyester of the present disclosure may include linear crystalline block copolymers such as diblock, triblock and pentablock copolymers, and is synthesized from a prepolymer which can be either amorphous or crystalline. In another embodiment, the aliphatic polyester of the present disclosure may include linear crystalline random or segmented copolymers, both synthesized in a single reaction step without a prepolymer. In a further embodiment, the aliphatic polyester of the present disclosure may include a multi-axial crystalline block copolymer (having at least 3 axes), and is synthesized from a triaxial prepolymer which can be either amorphous or semi-crystalline. In yet a further embodiment, the aliphatic polyester of the present disclosure may include a multi-axial, crystalline segmented or random copolymer, both synthesized in a single reaction step without a prepolymer. In yet a further embodiment, the polyester may be synthesized from cyclic monomers such as glycolide, lactide, para-dioxanone, trimethylene carbonate, ε-caprolactone, morpholine dione, and mixtures thereof. In yet a further embodiment, the polyester may be synthesized from an initiator compound containing from 1 to at least 3 hydroxyl groups capable of initiating ring-opening polymerization. In a further embodiment, the polyester may be a high glycolide copolymer containing a small amount of at least one additional monomer. "High" means that the polymer may contain at least 50 mol% glycolide-derived repeating units, at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more glycolide-derived repeating units. Ranges of the molar content of glycolide are also contemplated by the present disclosure including ranges of 50-60%, 60-70%, 70-80%, 80-90%, and 90-100%.

[0012] In a preferred embodiment, the high-glycolide copolymer may be a highly crystalline multiaxial block copolymer, which is synthesized in two steps. The copolymer may contain a triaxial amorphous prepolymer and high-glycolide crystalline end grafts extending from each end of the three prepolymer arms. In a further preferred embodiment, the high-glycolide copolymer may be a highly crystalline multiaxial block copolymer, which contains a triaxial crystalline prepolymer and high-glycolide crystalline end grafts extending from each end of the three prepolymer arms. In yet another preferred embodiment, the high-glycolide copolymer may be a highly crystalline multiaxial segmented copolymer, which is synthesized in a single reaction step without the synthesis of a prepolymer. Furthermore, since the segmented copolymer lacks a prepolymer, there are no distinct "blocks" within the polymer structure. In a further embodiment, the polyester may be a high-lactide copolymer containing a small amount of at least one additional monomer. "High" means that the polymer may contain at least 50 mol% lactide-derived repeat units, and at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more lactide-derived repeat units. The disclosure also implies a range of lactide molar content including 50-60%, 60-70%, 70-80%, 80-90%, and 90-100%.

[0013] In a further preferred embodiment, the high-glycolide copolymer may be a highly crystalline multiaxial block copolymer synthesized in a two-step process, which requires the synthesis of a crystalline prepolymer from caprolactone and trimethylene carbonate, followed by terminal grafting of the prepolymer with glycolide and caprolactone to obtain the final block copolymer. This composition contains four different blocks: a central crystalline block with three axes and three crystalline terminal graft blocks extending from each of the three chain ends of the central block. The absorbent copolymers of the present disclosure can be formed by a method that includes ring-opening polymerization conducted in the solid state and / or in the molten state. In a preferred method, the absorbent copolymers of the present disclosure may be synthesized in melt, and it is necessary to conduct the reaction at a temperature higher than the melting temperature of the copolymer being synthesized. In other preferred methods, the absorbent copolymers of the present disclosure may be synthesized in the solid state, or the reaction may be terminated when the reaction product becomes too thick and / or begins to crystallize to agitate. Ring-opening polymerization (``ROP'') conducted in the molten state and in a large reactor such as an 8CV reactor is superior to solid-state synthesis for forming the copolymers of the present application, particularly when a batch size larger than 1 kilogram is desirable.

[0014] In one embodiment, the reaction may be carried out by filling an 8CV reactor with monomers and an initiator, then heating the reactor to 100°C under nitrogen (g) system, then stirring the molten monomers and initiator to produce a homogeneous mixture, and finally adding a catalyst to raise the reaction temperature above the melting temperature of the polymer being synthesized. The contents of the reactor are stirred "with the molten material," and the reaction is allowed to proceed until the maximum conversion of the monomers into the polymer is reached. Then, when the maximum conversion is reached, the molten polymer is removed from the bottom of the reactor. This synthesis technique is commonly referred to as the "molten" technique. Solid-state synthesis, on the other hand, limits the amount of polymer that can be synthesized in any single batch. However, by utilizing a larger reactor suitable for ROP in the molten state, the polymer may be produced in 7.5-kilogram batches in an 8CV reactor, or on a much larger scale than 7.5 kilograms for larger reactors. This is in comparison to solid-state reactions carried out in smaller reaction vessels such as 1-liter kettles. The reaction initiator may include a compound having 1 to 3 hydroxyl groups capable of initiating ring-opening polymerization. Examples include, but are not limited to, 1-decanol, 1,3-propanediol, trimethylolpropane, triethanolamine, 1,3,4-trihydroxy-2-butanone, and glycerol, or combinations thereof. On the other hand, a preferred catalyst for these ROP reactions is stannous octanoate. However, other catalysts known to those skilled in the art may be used. The polymers obtained from the methods disclosed herein may or may not have a linear or multiaxial copolymer structure, and they may be either segmented or block copolymers. Therefore, prepolymers may or may not be used in the synthesis of the copolymers described herein.

[0015] Figure 1 is a graph showing the thermogravimetric analysis (TGA) of the polymer of the present invention. Semicrystalline linear block copolymers were tested. Triblock copolymers having intermediate blocks derived from prepolymers and semicrystalline terminal grafts were also tested, not intended to be limited to examples only. In one embodiment, the prepolymer contained TMC and caprolactone, and the terminal graft contained l-lactide and TMC. As shown in Figure 1, in this disclosure, increased thermal stability is achieved by decreasing the catalyst content. The catalyst amount is expressed as the ratio of moles of catalyst to moles of monomer, where the number of moles of catalyst is the denominator; therefore, a larger ratio means less catalyst. In Figure 1, the three curves represent different polymer compositions, each with a different amount of catalyst (viewing the graph from left to right, M / C values ​​are 20,000, 25,000, and 40,000). Furthermore, as shown in Figure 1, each composition has a different temperature at which decomposition begins. Thus, the thermal stability of the polymers in this disclosure improves as the amount of catalyst decreases. For example, T3 has the least amount of catalyst, T2 has the next least, and T1 has the most catalyst in the polymer. Thermogravimetric analysis (TGA) was performed using a constant heating method, heating from 20°C to 550°C at a rate of 20°C / min under a nitrogen environment. All samples were dried at room temperature and under reduced pressure of less than 0.2 Torre for one week. Under these constant conditions, the effects of residual monomer content and catalyst concentration on thermal stability were separated. Four lots of unoptimized high-lactide copolymers were analyzed by TGA to determine the decomposition onset temperature. Furthermore, 35 lots of unoptimized high-lactide copolymers were analyzed before and after extrusion to determine the retention of intrinsic viscosity (IV) after extrusion. The results are shown in Table 1 below.

[0016] [Table 1]

[0017] In one embodiment, a lactide-based copolymer (more specific) reaction is carried out at two independent reaction temperature settings, where only high temperatures result in a low conversion rate (conversion rate <92%) and only low temperatures result in an excessive reaction time (>150 hours). The overall reaction, with a combination of two independent reaction temperatures above and below the molten material, results in a conversion rate of >92% and a reaction time of <150 hours. The first reaction temperature is higher than the molten material, and the reaction is completed in the molten state. The second reaction temperature is carried out in the solid state, and the polymer crystallizes. The reaction temperatures above and below the molten material must differ from the solid state reaction temperature by at least 5°C, preferably 5-10°C, more preferably 10-20°C, and even more preferably >20°C. The reaction temperature was measured using a thermocouple to determine the bath temperature. Under these conditions, the polymer is reacted in a batch process, and there is no change in the reaction vessel. A change in vessel type introduces potential contamination such as moisture.

[0018] In another embodiment, the monomer-to-catalyst ratio of the prepolymer must be sufficiently high so that the total monomer-to-catalyst ratio after the addition of a second monomer filler having >50% lactide for the crystalline segment is higher than an M / C of 25,000, more preferably >30,000, even more preferably >50,000, and even more preferably >100,000. Lower M / C values ​​result in premature reaction between the prepolymer and the monomers prepared for the terminal grafts in subsequent reaction steps, as described in the methods for synthesizing block copolymers of this disclosure. Early reactions prevent the complete dissolution of the prepolymer into the liquid monomer, which is necessary for homogeneity before forming terminal block / terminal graft polymer chains on the prepolymer. The resulting change in solubility prevents the complete dissolution of the prepolymer, and therefore contains a mixture of block copolymer and the remaining undissolved prepolymer that could not react with the monomer in the second filler. This result is confirmed by visual heterogeneity or by GPC analysis, as shown as shoulder peaks in Figure 9. Optionally, more catalyst may be added to the reaction vessel after the complete dissolution and mixing of the prepolymer and the second filler, resulting in a decrease in M / C. In reactions such as these, where the catalyst is supplied in two or more steps during polymerization, an M / C greater than 115K, 125K, 150K, 175K, 190K, 200K, or 215K is required. The prepolymer may optionally react with additional monomers to form flexible bond segments, and subsequently react with a third monomer or mixture of monomers to form terminal blocks. In both the second and third grafting reactions, it is desirable to have a consistent degree of polymerization for each polymer arm of the block copolymer, as well as a similar degree of polymerization for the polymer chains of the bulk composition in the reactor. For GPC analysis, multimodal results are observed when there is essentially a blend of prepolymers that are either unreacted or partially reacted with the block copolymer, which consists of prepolymers and terminal graft blocks. The prepolymers are inconsistent; some parts react, while others do not react with the second packing of monomers. This results in a blended composition of different polymers, which may even be amorphous polymers distributed within the desired polymer.

[0019] Preferred catalysts for ring-opening polymerization include organotin compounds such as tin(II)2-ethylhexanoate and dibutyltin oxide, but other alternatives are also included. Furthermore, suitable initiators for ring-opening polymerization include hydroxyl-containing small molecules, oligomers, polymers, inorganic salts, and organic salts. Initiators may be in the form of small molecules with an average molar mass of less than 1000 g per mole, less than 500 g per mole, or less than 300 g per mole, and the molar mass of the initiator is comparable to the average molar mass of a single monomer (cyclic monomers such as lactones and carbonates typically have an average molar mass between 100 g and 200 g per mole). In some embodiments, the initiator comprises a single hydroxyl group or amine group, or two or more hydroxyl groups or amine groups, or at least one amine group in combination with one or more hydroxyl groups. The initiator may also be in the form of a monofunctional hydroxyl or amine species, a polyol or polyamine having two or more reactive groups, or a hydroxyl-amino compound comprising one or more hydroxyl groups and one or more amino groups. Suitable initiator combinations disclosed herein may be used in a single reaction to synthesize mixtures of different polymers having different configurations but still possessing repeating units of the same overall chemical composition.

[0020] In some embodiments, the catalyst may serve as an initiator for ring-opening polymerization of cyclic monomers, including but not limited to lactones, carbonates, and morpholindiones. Non-limiting examples of suitable monomers include lactides such as L,L-lactide and D,L-lactide, glycolides, substituted glycolides, para-dioxanone, 1,5-dioxepant-2-one, trimethylene carbonate, epsilon-caprolactone, alpha-angelicalactone, gamma-valerolactone, and delta-valerolactone. Additional monomers suitable for use in some embodiments include 5-membered and 7-membered cyclic esters, carbonates, and amides (e.g., cyclic amide esters, also known as morpholindiones), which may be present in combination. Substitutive glycosides referenced in this disclosure may have side chain groups other than protons on one or both methylene (-CH2-) carbons. Non-limiting examples of substituents include: saturated hydrocarbons having at least two carbons, which may be linear or branched and may be functionalized; some functional groups require protection prior to ring-opening polymerization, followed by deprotection upon completion of polymerization; other functional groups do not interfere with the polymerization reaction and do not require protection / deprotection; and some desirable functional groups may participate in polymerization to induce secondary reactions such as branching of the main polymer chain axis, thereby enabling the formation of unique polymer structures such as superbranched polymers.

[0021] Suitable additional substituents for modifying glycolides may include aromatic groups having at least one carbon that separates the aromatic group from the methylene carbon of the ring (to cause separation between the aromatic ring and the reaction site of the ring to prevent a significant decrease in reactivity). Other useful substituents may include unsaturated hydrocarbons having one or more carbon-carbon double bonds, where the unsaturation may be located at the terminal (i.e., vinyl-terminated) or internally, and where the unsaturated hydrocarbon may be aliphatic or aromatic. Furthermore, halogens such as bromine and iodine may be used as suitable substituents—they may act as good leaving groups for secondary reactions during or after polymerization, and halogens may confer radiopaqueness if halogen atoms are present in sufficiently high concentrations along the polymer chain.

[0022] Furthermore, the substituents may exist as single substituents on the glycolide ring, or they may exist in various combinations. For example, they may be found overlapping and on the same or opposite (para) carbon. Alternatively, two chemically different substituents may be present on the same ring, and the substituents may be on the same or different carbons. Since the methylene carbon of the glycolide exhibits sp3 hybridization, each of the two protons on the methylene carbon may be substituted as disclosed herein. Furthermore, the same or different substituents may be found on the same carbon. The chirality of the substituted glycolide is determined by the arrangement of substituents along the ring. In another embodiment, the prepolymer must be heated to a minimum of 110°C, more preferably >115°C, more preferably >120°C, and even more preferably >130°C in order to dissolve in the second filler.

[0023] In further embodiments, the glycolide-based copolymer must be sufficiently large such that the monomer-to-catalyst ratio of the prepolymer is greater than 90,000, more preferably >100,000, even more preferably >150,000, and even more preferably >200,000, after the addition of the second monomer filler with >50% glycolide of the crystalline segment, resulting in an M / C ratio of the total monomer-to-catalyst ratio greater than 90,000. The high monomer-to-catalyst ratio in the prepolymer leads to an early reaction of the prepolymer to the second filler, and therefore a change in solubility. The resulting change in solubility prevents the complete dissolution of the prepolymer, and thus a heterogeneous polymer having a mixture of block copolymer that could not react with the monomer in the second filler and the remaining undissolved prepolymer. This result is confirmed by visual heterogeneity. Optionally, more catalyst is added to the reaction vessel after the complete dissolution and mixing of the prepolymer and the second filler, resulting in a decrease in M / C. In reactions like these, where the catalyst is supplied in two or more steps during polymerization, it is necessary for M / C to be greater than X to achieve complete solubility and homogeneity. In another embodiment, the molecular weight of the prepolymer must be greater than 10 kDa, more preferably >15 kDa, and even more preferably >20 kDa. In another embodiment, the molecular weight of the prepolymer must be greater than 10 kDa, more preferably >15 kDa, even more preferably >20 kDa, even more preferably >30 kDa, even more preferably >50 kDa, and even more preferably >60 kDa (including the source). The molecular weight of the prepolymer is determined by GPC. The development lots synthesized for this disclosure used a low catalyst concentration. The reaction temperature and time were modified to account for this change. Due to the lower catalyst concentration and new reaction conditions, a decrease in the conversion rate of the optimized high lactide copolymer and an increase in the remaining monomer content were expected. The reaction conditions for each optimized lot are listed in Table 2 below.

[0024] [Table 2]

[0025] Table 3 below shows data comparing the area under the curves of the tested polymers and monomers using gel permeation chromatography (GPC). All optimized lots have high residual monomer content under the new reaction conditions. Lots 2d-4d have significantly high residual monomer content. Lot 2d shows improved conversion (lots 3d and 4d) by reacting it under two independent temperature settings, one in the molten state and the other in the solid state with a 20°C temperature difference. This result is shown in Table 3 by the reduction in residual monomer in lots 3d and 4d.

[0026] [Table 3]

[0027] Table 4 shows the molecular weight and remaining monomer content after devolatilization for the control and optimized lots. The modified devolatilization procedure reduced the remaining monomer content below the control value, and the average remaining monomer content in the optimized lots was less than 1% by mass. Lots 1d and 4d, containing high lactide block copolymer and labeled as SMC22, both had an out-of-spec IV of >2.4 dL / g. Furthermore, the PDI of each optimized lot with reduced catalyst concentration decreased.

[0028] [Table 4]

[0029] Table 5 below shows the Melt Flow Index (MFI) results for the optimized and control lots. MFI is generally used to predict initial extrusion settings. Many properties of aliphatic polyesters, including polymer molecular weight, residual monomer content, water content, temperature, pressure, and catalyst concentration, affect MFI. The method performed consisted of a constant temperature of 205°C and a constant mass of 3800 grams. In optimized lots 2d-4d, the catalyst concentration and drying conditions remained constant. In these samples, the differing MFI values ​​were a product of lot-to-lot variations in molecular weight and residual monomer concentration. Typically, melt viscosity is expected to be directly related to the molecular weight of the polymer (melt viscosity typically increases with increasing molecular weight). Furthermore, the residual monomer content acts as a plasticizer, reducing the melt viscosity. Comparing lot 4d with lots 3d and 2d, it is clear that although the molecular weights of lots 3d and 2d are higher than that of lot 4d, the melt viscosities of lots 3d and 2d are lower, as indicated by the MFI results. Therefore, the lower monomer content in lot 4d appears to increase the melt viscosity by reducing the plasticizing effect of the monomers. In summary, while melt viscosity typically increases with increasing molecular weight, here we observed that the presence or absence of residual monomer content leads to an increase in the melt viscosity of low molecular weight polymers.

[0030] [Table 5]

[0031] The results for the decomposition onset temperature are shown in Table 6 below. Each polymer was dried under constant conditions. Comparing lot 1d with lot 4d, it is clear that lot 1d had a lower decomposition onset temperature (326.5°C) than lot 4d (347.8°C). The polymers of both lots had similar residual monomer content, but lot 4d had less catalyst and a monomer-to-catalyst ratio of 40,000 compared to 25,000 for lot 1d. In this example, the increase in thermal stability of lot 4d is indicated by a rise in the onset temperature of only 21.3°C. Comparing lot 4d with the control, lot 4d had considerably less catalyst and residual monomer, and the onset temperature of lot 4d was only 28.1°C higher than the control. The TGA graphs for the control, lot 1d, and lot 2d are shown in Figure 1. The effect of increasing thermal stability is supported by shifting the curve to the right, thereby increasing the decomposition onset temperature.

[0032] [Table 6]

[0033] [Table 7]

[0034] Multiple embodiments are possible with respect to the present disclosure. For example, Figures 6A and 6B illustrate two embodiments of the present disclosure. Figure 6A shows a fully extended chain of a semi-crystalline multiaxial block copolymer, in which both the terminal graft segments and the internal prepolymer-derived segments are crystallizable. Figure 6A shows one embodiment of a semi-crystalline terminal graft 20 of a multiaxial block copolymer 22 and a semi-crystalline prepolymer 24. In another embodiment, Figure 6B shows another embodiment of the present disclosure. Figure 6B shows an amorphous (non-crystallizable) multiaxial core 26 comprising three polymer amorphous arms 28, each having a crystallizable terminal graft 30. Figures 7A and 7B illustrate two further alternative embodiments of the polymer constructs of the present disclosure. For 7A and 7B, the illustrated prepolymers may be amorphous or crystallizable. Figure 7A shows a multiaxial block copolymer 32 without a flexible linker connecting prepolymer to a terminal graft 36. The cross marks 38 represent not only the junction between the prepolymer 34 and the terminal graft 36, but also the fully extended theoretical stereostructure of the arm 40 of the prepolymer 34. Figure 7B shows a polymer construct 40 having a flexible linker 42 between a block 44 derived from the prepolymer 46 and a terminal graft 48 having a core 50 derived from the prepolymer 46, the core 50 may be amorphous or crystallizable. The terminal graft 48 may be amorphous or crystallizable. The flexible linker 42 has a minimum of 10 repeat units and may be derived from TMC in combination with other monomers described herein.

[0035] Figure 8 shows the chemical structure of repeating units that form copolymers derived from glycolide and trimethylene carbonate (the copolymer represented by elements 11, 12, and optionally 13 in Figure 11). Figure 10 shows an analysis of one embodiment of the polymer in Figure 8. X represents the glycolide-derived repeating unit, and Y represents the trimethylene carbonate-derived repeating unit. In one embodiment, the molar ratio of the chemical structures is X + Y = 1.0, with X being approximately 0.333 and Y approximately 0.667. As shown in the figure, approximately 33 mol% and 67% (molar ratio) of repeating units are derived from glycolide and trimethylene carbonate, respectively. The omitted polymer structures shown in Figure 8 and on a larger scale in Figure 11 may be synthesized in bulk or in solution, and the reaction is carried out in the presence of an initiator and a catalyst, optionally in combination with an inert organic solvent for solution polymerization. In a preferred embodiment, the polymer is synthesized in bulk by ring-opening polymerization using tin(II)2-ethylhexanoate as a polyol initiator and catalyst. Preferably, the polyol has three or more reactive hydroxyl groups so that polymerization can yield a polymer having a star structure with three or more different polymer arms (the exact number of polymer arms or chains is equal to the number of reactive hydroxyl groups represented by the initiator). It is desirable that the polyol exhibits symmetry and that the hydroxyl groups have identical or very similar reaction rates, which helps ensure that similar chain lengths are obtained for each polymer arm (as shown in Figure 11). Triethanolamine is an example of a polyol suitable for synthesizing the three-armed star copolymer shown in Figure 11.

[0036] Figure 11 is a diagram identifying the terminal block 14 of one of the three arms 11 of a multiaxial block copolymer 15, as well as the prepolymer segment 12 and flexible linker 13. In one embodiment, the terminal block 14 is preferably formed entirely from glycolide-induced repeating units, so that the terminal block can form highly crystalline physical crosslinks with the terminal blocks of other star-shaped block copolymers. In contrast, the prepolymer 16 may be formed from the prepolymer segment 12 and the flexible linker 13. The prepolymer 16 is intended to be an elastomer and must exhibit minimal crystallinity or preferably amorphous. The flexible linker segment 13 may be covalently bonded to the prepolymer segment 12 and the terminal block 14 for each arm 11. The flexible linker 13 is preferably a short linker segment of poly(trimethylene carbonate) that is amorphous overall. On the other hand, both arm 11 and prepolymer segment 12 are poly(glycolide-co-trimethylene carbonate), but in one embodiment, arm 11 may contain a higher proportion of glycolide-derived repeating units than prepolymer segment 12. Due to the difference in reaction rates between glycolide and trimethylene carbonate (glycolide reacts faster), the chemical composition of the prepolymer should have a decreasing glycolide content as it moves outward along the polymer chain until it reaches the terminal poly(glycolide) block. Therefore, once synthesis is initiated, both glycolide and trimethylene carbonate react until all glycolide has reacted, and then only trimethylene carbonate continues to react.

[0037] As the amount of glycolide decreases during the reaction, the segment represented by prepolymer segment 12 is synthesized, and if a considerable amount of trimethylene carbonate remains, the bonded segment 13 may be formed without requiring the addition of more trimethylene carbonate to the reaction vessel in the first reaction step. This situation is more likely to occur when the prepolymer is synthesized in the presence of a smaller amount of catalyst, as preferably taught by the present disclosure, and this mismatch in composition along the polymer chain is more likely to occur when the reaction is carried out at low temperatures, where the difference in reaction rates of the monomers is more apparent. However, if a higher reaction temperature is used during prepolymer synthesis, a greater degree of randomization occurs, resulting in a more uniform distribution of the glycolide. Next, to synthesize the flexible bond segment represented by bond segment 13, it is necessary to add additional trimethylene carbonate to the reaction vessel and carry out a second reaction step. In either of these two different scenarios, the final reaction step requires adding glycolide to the reaction vessel to graft the glycolide onto the prepolymer and to form terminal blocks on all three polymer chains. To successfully perform this polymerization, it is necessary to use a minimal amount of catalyst (preferably a total monomer to catalyst molar ratio of more than 150,000 is required, but a higher monomer to catalyst ratio, e.g., 200,000, is more preferable) especially when trying to achieve a high proportion of the prepolymer in the final polymer, as in Figure 11 where the prepolymer may account for 30-45% (preferably 35%) of the total polymer, and when the final reaction step requires raising the temperature after the prepolymer has completely dissolved in the molten glycolide to synthesize the terminal blocks. In a two-step reaction, elements 11, 12, and 13 are considered prepolymers. In a three-step reaction, elements 11 and 12 represent two different regions of different compositions in the prepolymer based on the difference in reaction rates. In both cases, in the two-step and three-step reactions, element 13 is considered a flexible linker.

[0038] Figure 12 shows an alternative embodiment of the multiaxial block copolymer 59 containing multiple segments. The segmented prepolymer 61 consists of random regions 60 and transition regions 62. 60 and 62 represent two different regions in the prepolymer, which in one embodiment contain most glycolide units (60) and transition regions 62 represent a case where fewer glycolide repeat units are formed mainly from a slower reaction rate. The flexible linker 64 may be formed in a separate reaction step after the synthesis of the segmented prepolymer 61. The terminal grafts 66 may optionally be high-glycolide or high-lactide terminal blocks. Figure 13 shows a four-armed multiaxial copolymer 80 including arms 82, 84, 86, and 88. All four arms 82, 84, 86, and 88 contain a microstructure 90. In one embodiment, arm 82 is a single arm of the four-armed multiaxial copolymer. Arm 82 may be a vertically oriented crystalline lamella composed of a number of individual arms of the same composition 92. Arms 82 and 86 may be crystalline, while 84 and 88 may be amorphous. Since 82 and 86 and 84 and 88 may have variable "widths", there is variable space between the arms. The chemical composition of the opposing arms in Figure 13 is substantially the same as in Figure 13. Figure 13 shows a four-armed multiaxial star polymer composed of two types of polymer arms - amorphous and semicrystalline. The four arms are oriented around a central vertical axis 94 extending through the center of the copolymer 80.

[0039] Figure 14 is an excerpt from Figure 13 showing the folding of an exemplary polymer chain arm 96, which results in a folded crystal. Thus, the semi-crystalline arms 82, 84, 86, and 88 in Figure 13 repute parallel or nearly parallel to the Z axis and outward from the Z axis as a crystalline lamellar morphology, as shown in Figure 14. An additional four-armed star polymer "stacks" vertically, contributing to crystal growth. The vertical incorporation of polymer chains results in the vertical stacking and growth of crystalline domains along the Z axis, as shown in Figure 13. Furthermore, amorphous domains are formed from combinations of chains extending outward from the Z axis and connected to the crystalline polymer chains, exiting the crystalline lamellae along the chains and entangling with the amorphous phase, often re-entering the crystalline microstructure, forming "loops" on the lamellar planes bonded to each other, forming an organized structure in which each of two similar arms is positioned opposite each other in the same plane. Figure 15 shows an asymmetric multiaxial copolymer 100. In the illustrated embodiment, two arms 102 and 104 have chemically similar compositions, while a third arm 106 has a different chemical composition. Arm 102 consists of an internal amorphous block 108 formed as one arm of the prepolymer 112 and an external semicrystalline block 110 covalently bonded thereto. Arm 106, which can be formed in a different reaction step other than arms 102 and 104, may be formed in a first reaction step, followed by a second reaction step to form arms 102 and 104. Alternatively, arm 106 may be formed as part of an initial reaction step, and arms 102, 104, and 106 have chemically similar compositions. For example, a two-step reaction may be used to form a three-arm amorphous prepolymer, in which one terminal hydroxyl group may be protected on the surface or optionally fixed to the surface before a second reaction step requiring ring-opening polymerization to terminally graft terminal crystallizable blocks onto two unprotected prepolymer arms.

[0040] Figure 16 shows a single microstructure 120 representing individual polymers 122 that can be considered hyperbranched. The core 124 is formed by unoriented amorphous irregular polymer chains 126 that begin at a central position 128, essentially or substantially at the center of the microstructure 120, where the unoriented polymer chains 126 transition to an external semi-crystalline block 130. The block 130 may crystallize as shown in Figure 14 by the chains forming a folded crystalline structure. The microstructure 120 of Figure 16 may be used as a drug delivery system to disperse a bioactive agent (not shown) within the structure of the chains 126 via the large void volume 125 of the chains 126. The size and concentration of the bioactive agent that can be filled into the core 124 depends on the number of polymer chains 126, which directly affects the overall available void volume that can be occupied by the bioactive agent. The outer shell 132, through chain folding of the semicrystalline block 130, forms a tough protective shell that acts as a protective layer for the internally dispersed voids 125 and the bioactive agent. The bioactive agent may be substantially contained within the voids 125 until the shell 132 has sufficiently decomposed to allow sufficient porosity for the diffusion of the bioactive agent through the shell 132. The shell 132 may be designed to allow initial bioactive release, followed by increased bioactive release as the shell further decomposes. It is preferable to avoid defects in the shell to provide protection for the voids 125. In a preferred embodiment, the terminal block 130 may be synthesized using a single monomer to allow for a uniform crystalline structure. Multiple microstructures 120 may be used together, overlapping each other in the shell 132 to form crystalline domains between adjacent microstructures 120. The microstructures 120 may be formed in a film or used as individual spheres to allow for the dispersion of the bioactive agent in a desired form over a desired time span.

[0041] In other preferred embodiments, it is desirable to form different polymer structures such as linear (unidirectional and bidirectional), multiaxial, star-shaped, branched, grafted, comb-shaped, brush-shaped, circular, and combinations thereof. However, since it is necessary to improve the thermal stability of the copolyester, the same concept of using minimal catalysts is still required (in addition to promoting homogeneous mixing of the prepolymer and monomer as the second / final reaction step), so that the polymer can be processed at a temperature higher than the melting point without causing extreme or significant decomposition. Absorbent fibers may be produced from the polymers of this disclosure by melt extrusion and electrospinning techniques, as is known to those skilled in the art. These fibers may be formed into solid structures such as barriers, webs, meshes, or fabrics (woven or nonwoven) by methods known to those skilled in the art. Alternatively, partially absorbent structures may be formed by combining absorbent polymers and fibers derived therefrom with non-absorbent fibers derived from materials such as polyurethane, polypropylene, polyethylene, polyetheretherketone (PEEK), and polyethylene terephthalate.

[0042] In one embodiment, the mesh may be constructed by warp knitting and weft knitting. Specific knitting patterns may be selected according to the mechanical strength requirements of a particular medical application. Hybrid structures can also be fabricated by combining different techniques for forming fibrous structures in unique ways. For example, electrospinning can be performed on a warp-knitted mesh to obtain an electrospun surface or layer. In fact, the polymers of the Disclosure are suitable as medical-grade polymers for incorporation into a variety of medical devices, such as absorbent or partially absorbent meshes, pouches, containers, barriers, and support structures, which may be formed from the polymers of the Disclosure. For example, Figure 2 shows one embodiment of the present disclosure in which a warp-knitted 3-bar structure may be used. The 3-bar pattern may be advantageous in terms of improved dimensional and mechanical properties, particularly in terms of improved stability in the weft direction. Furthermore, the 3-bar pattern typically produces a "heavier" fabric. In one embodiment, a fabric made using a warp-knitted 3-bar structure may be used for sealing applications. In one embodiment, a 3-bar configuration of bar 1: 1-0-0 / 0-1-1, bar 2: 2-3-2 / 1-0-1, and bar 3: 1-0-1 / 1-2-1 may be used. On the other hand, Figure 3 shows one embodiment of the present disclosure in which a warp-knit 2-bar structure may be used. In one embodiment, a tricot fabric may be manufactured. Tricot has a simple structure and provides a lightweight fabric with a short underwrap. In one embodiment, a 2-bar configuration including bar 1: 1-2 / 1-0 and bar 2: 1-0 / 1-2 may be used.

[0043] Figure 4 shows another warp-knit 2-bar structure known as "sharkskin." Although sharkskin is a simple 2-bar structure, it has a longer swing distance, which results in increased stability and increased area density. Furthermore, the sharkskin pattern exhibits reduced shrinkage potential. Thus, it gives a more rigid and stable structure. In addition, the surface texture of the sharkskin structure is "rough," making it suitable for medical applications where adhesion is desired. In one embodiment, a 2-bar structure may be used, where bar 1: 1-2-2 / 1-0-0 and bar 2: 1-0-1 / 3-4-3. Figure 5 shows a half-tricot pattern that may be used in this disclosure. The half-tricot pattern results in a low surface density structure, thereby giving it a very light structure. It is not as strong as tricot, but it is easy to manufacture, requires less material, and has a simple structure. In one embodiment, a structure with bar notation 1-2 / 1-0 may be used. This is an example of a half-tricot pattern, where "1-2" means that the guide bars overlap when moving from right to left for one needle from position 1 to position 2. "1-0" means feeding the needle from left to right.

[0044] Figures 6A and 6B show a multiaxial structure of an absorbent block copolymer comprising a prepolymer which may be amorphous or crystallizable, and a structure further comprising a flexible binding segment between the polymer axis and the terminal grafted end block derived from the prepolymer. The suitable flexible binding segment may be derived from trimethylene carbonate and epsilon-caprolactone in any combination. When epsilon-caprolactone is selected as the flexible binding segment, it is necessary to ensure that the segment remains amorphous and that the chain length does not exceed the crystallization threshold of caprolactone. In one preferred embodiment, the prepolymer is derived from glycolide and trimethylene carbonate and is amorphous, the flexible binding segment is derived from trimethylene carbonate, and the terminal grafted block is derived from glycolide. Optionally, flexible linkers may be formed as a result of reaction parameters that allow excess trimethylene carbonate to remain during the first polymerization reaction forming the prepolymer, so after the prepolymer is formed, the remaining trimethylene carbonate may react to form flexible linkers. A second method for forming linkers is to react the prepolymer at a high temperature to ensure randomization of the prepolymer and non-segmentation of the trimethylene carbonate at the ends of the prepolymer, followed by adding more trimethylene carbonate to the reaction vessel to form binding segments. Glycolide is added to the reaction vessel to form end graft blocks after the trimethylene carbonate has reacted to completion. The properties of polymers produced according to this procedure are shown in Table 8.

[0045] [Table 8]

[0046] In some embodiments, a barrier, web, mesh, or fabric that can be fully or partially absorbed according to the Disclosure may further include a method for delivering a therapeutic agent as well as one or more bioactive agents or therapeutic agents. This method includes the step of applying a mesh or web to a treatment site in which the mesh or web contains at least one type of polymer fiber and one or more bioactive agents and / or therapeutic agents. In some embodiments, the mesh or web may contain an absorbent polymer surface coating for controlled drug delivery, in which one or more bioactive agents and / or therapeutic agents are dispersed throughout the coating. Alternatively, the mesh or web may contain fibers impregnated with one or more bioactive agents and / or therapeutic agents (see, for example, U.S. Patent No. 8,128,954, which is incorporated throughout).

[0047] In some embodiments, the polymer surface coating may have multiple coatings or layers of absorbent aliphatic polyester, and the coating can be applied to a mesh surface. Different coating layers may contain the same or different bioactive and / or therapeutic agents, which are present in the same or different concentrations in each layer. In some embodiments, the coating consists of multiple layers, and there is a concentration gradient of bioactive and / or therapeutic agents from the innermost layer to the outermost layer, so that the concentration is highest in the innermost coating layer and lowest in the outermost coating layer. The bioactive and / or therapeutic agents may be dispersed in each of the coating layers, or they may be dispersed only in parts of the layers, or they may be dispersed in alternating coating layers, so that the alternating layers lack bioactive and / or therapeutic agents. Furthermore, the outermost layer may completely lack bioactive and / or therapeutic agents to reduce the possibility of burst release effects. When gradient concentration design is used to disperse one or more bioactive and / or therapeutic agents throughout the coating layers, it is preferable to have a concentration gradient that decreases from the innermost layer closest to the mesh surface to the outermost layer, which is the outermost of all layers. The concentration gradient is intended to reduce, if not eliminate, the initial burst release of bioactive and / or therapeutic agents from the coating surface shortly after mesh implantation.

[0048] In some embodiments, the coating polymer is a high molecular weight caprolactone-based copolymer in which caprolactone-derived repeat units constitute more than 50% of the repeat units in the total composition, and the remaining repeat units can be derived from monomers selected from L-lactide, glycolide, trimethylene carbonate, and para-dioxanone. When multiple coating layers constitute a surface coating on a mesh or web, each layer may be formed from the same or different caprolactone-based copolymers. Different copolymers are used when it is desirable to control the hydrophobic properties of different coating layers. Copolymers with a higher caprolactone content are more hydrophobic than copolymers with a lower caprolactone content. In some embodiments, it is desirable to have a compositional gradient in the different coating layers. For example, the innermost layer may be formed from a copolymer with 90 mol% caprolactone, followed by adjacent outer layers with 80%, 70%, and 60%, respectively, so that the caprolactone content (and hydrophobic properties) decreases from 90% to 60% from the innermost to the outermost layer. The coating polymer of the present invention is a copolymer of caprolactone and trimethylene carbonate.

[0049] In further embodiments, the prepolymer may comprise a semicrystalline aliphatic polyester copolymer having a heat of fusion of <75 J / g, preferably <70 J / g, more preferably <65 J / g, even more preferably <55 J / g, even more preferably <45 J / g, and even more preferably <35 J / g, as measured by DSC. The prepolymer may comprise cyclic monomers such as glycolides, lactides, para-dioxanones, trimethylene carbonates, morpholindiones, and mixtures thereof. The melting point of the prepolymer may be <170°C, more preferably <150°C, even more preferably <120°C, and even more preferably <100°C, as measured by DSC. The resulting prepolymer may be reacted with a flexible linker before crystalline end grafts. The flexible linker comprises at least 10 repeating units, more preferably >20, even more preferably >30 repeating units, and even more preferably >40. The flexible linker may include an amorphous segment and a composition containing cyclic monomers such as glycolide, lactide, para-dioxanone, ε-caprolactone, trimethylene carbonate, morpholindione, and mixtures thereof. The crystalline end graft may be a high lactide copolymer containing small amounts of at least one additional monomer. "High" means that the polymer may contain at least 50 mol% lactide-derived repeat units, and at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more lactide-derived repeat units. The molar content of lactide is also assumed to fall within the scope of this disclosure, including ranges of 50-60%, 60-70%, 70-80%, 80-90%, and 90-100%. Furthermore, the crystalline end graft may contain at least 50 mol% of glycolide-derived repeat units, and at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, and 95% or more of glycolide-derived repeat units. (See Figure 12) The molar content of glycolide is also assumed to fall within the scope of this disclosure, including ranges of 50-60%, 60-70%, 70-80%, 80-90%, and 90-100%. (See Figure 12) The entire polymer may contain a linear or multiaxial initiator.

[0050] In further embodiments, a second polymer may be combined with or blended with the improved block copolymer of the Disclosure. The second polymer may be a reinforcing additive that gives higher strength to the composition containing the block copolymer. This is particularly suitable when the amount of prepolymer present in the block copolymer exceeds 25% by mass of the total polymer, and even more so when the prepolymer approaches 50%. The additional polymer can actually crystallize the block copolymer, which would otherwise not be able to crystallize to the extent necessary to give the desired mechanical strength, in the presence of the additive. This results in a higher degree of crystallinity or crystallinity percentage of the blended composition. Furthermore, the reinforcing polymer may have a chain length about twice the chain length of a single terminal block of the block copolymer. The additional reinforcing polymer may not have to have a shorter chain length as it does not reinforce the block copolymer by forming physical entanglements between two or more terminal blocks of the block copolymer disclosed herein, which may be linear or multiaxial. The reinforcing polymer may have the same theoretical chemical composition and therefore may be derived from the same monomer as the repeating units that form the terminal blocks of the block copolymer. The polymerization of the terminal blocks may include remaining monomers from the reaction that forms either a prepolymer or a flexible bond segment.

[0051] Applying a surface coating to a mesh structure can be achieved by immersion coating or spray coating techniques using a liquid solution of a polymer mixed with one or more therapeutic agents at specific concentrations. Alternatively, the liquid solution may contain a polymer without therapeutic agents. Mixing and dissolution can be achieved by combining a caprolactone-based coating polymer with a common organic solvent and a specific amount of therapeutic agent. This yields a solution with a specific concentration of therapeutic agent that can be applied to the mesh surface by immersion coating or spray coating. Different solutions can be applied sequentially to the mesh surface to form multiple coating layers. Since each solution may contain one or more therapeutic agents at different concentrations, a concentration gradient can be created across the entire surface coating, and / or each solution may contain polymers with different hydrophobic properties. In alternative embodiments, a biocompatible polymer composition containing a therapeutic agent can be prepared by cold working or hot working, depending on the heat resistance of the therapeutic agent. Cold working is preferred for therapeutic agents that are easily inactivated by heat. In general, the polymer components of the mesh or web, the main component, the minor component, or both, can be completely melted in the absence of the therapeutic agent. The molten composition is cooled to below room temperature to delay the crystallization of the polymers in the composition. In certain embodiments, cooling is carried out at a rate of about 10°C per minute. The therapeutic agent is then added to the molten composition at below room temperature and thoroughly mixed with the composition to produce a homogeneous blend. Depending on the type of material, a solution-based mixing procedure may be used.

[0052] In alternative embodiments, the barriers, meshes, or webs of this disclosure may have bioactive agents and / or therapeutic agents applied to one or more specific portions of the mesh or web, in contrast to the entire structure. Within the scope of certain embodiments, the mesh or web may be immersion-coated or spray-coated with one or more bioactive agents or with a composition that releases one or more bioactive agents over a desired time frame. In yet another embodiment, the fibers themselves may be configured to release bioactive agents (see, for example, U.S. Patent No. 8,128,954, incorporated herein by law). Therapeutic agents may include fibrosis inducers, antifungal agents, antibacterial agents, anti-inflammatory agents, anti-adhesion agents, bone formation promoters, calcification promoters, antibacterial agents, antibiotics, immunosuppressants, immunostimulants, antiseptics, anesthetics, antioxidants, cell / tissue growth factors, lipopolysaccharide complexing agents, antiscarring agents, antineoplastic agents, anticancer agents, and agents that support ECM integration.

[0053] Examples of fibrosis-inducing agents include talc powder, beryllium metal and its oxides, copper, silk, silica, crystalline silicates, talc, quartz powder, and ethanol; extracellular matrix components selected from fibronectin, collagen, fibrin, or fibrinogen; polymers selected from the group consisting of polylysine, poly(ethylene copolymer acetate), chitosan, N-carboxybutyl chitosan, and RGD protein; vinyl chloride or polymers of vinyl chloride; cyanoacrylate and cross-linked poly(ethylene glycol)-methyl Adhesives selected from the group consisting of ionized collagen; inflammatory cytokines (e.g., TGF-beta, PDGF, VEGF, bFGF, TNF-alpha, NGF, GM-CSF, IGF-α, IL-1, IL-1-β, IL-8, IL-6, and growth hormone); connective tissue growth factor (CTGF); bone morphogenetic proteins (BMPs) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7); leptin, and bleomycin or analogues or derivatives thereof. Optionally, the device may further contain growth-promoting agents that stimulate cell proliferation. Examples of growth agents may include dexamethasone, isotretinoin (13-cisretinoic acid), 17-e-estradiol, estradiol, 1-α-25-dihydroxyvitamin D3, diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid (ATRA), and analogs and derivatives thereof (see U.S. Patent Application Publication 2006 / 0240063, which is incorporated throughout).

[0054] Examples of antifungal agents include, but are not limited to, polyene antifungals, azole antifungals, and echinocandin. Examples of antibacterial agents and antibiotics include, but are not limited to, erythromycin, penicillin, cephalosporins, doxycycline, gentamicin, vancomycin, tobramycin, clindamycin, and mitomycin. Examples of anti-inflammatory drugs include, but are not limited to, nonsteroidal anti-inflammatory drugs such as ketorolac, naproxen, diclofenac sodium, and flurbiprofen. Examples of anti-adhesion agents include, but are not limited to, talc powder, beryllium metal and its oxides, copper, silk, silica, crystalline silicates, talc, quartz powder, and ethanol. Examples of bone formation or calcification promoters include, but are not limited to, hydroxyapatite, tricalcium phosphate, calcium chloride, calcium carbonate, calcium sulfate, bioactive glass, and bone morphogenetic proteins (BMPs), such as BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. Examples of immunosuppressants include, but are not limited to, glucocorticoids, alkylating agents, antimetabolites, and immunophilin-acting agents such as cyclosporine and tacrolimus.

[0055] Examples of immunostimulants include, but are not limited to, interleukins, interferons, cytokines, Toll-like receptor (TLR) agonists, cytokine receptor agonists, CD40 agonists, Fc receptor agonists, CpG-containing immunostimulatory nucleic acids, complement receptor agonists, or adjuvants. Examples of preservatives include, but are not limited to, chlorhexidine and tibezonium iodide. Examples of antioxidants include, but are not limited to, antioxidant vitamins, carotenoids, and flavonoids. Examples of anesthetics include, but are not limited to, lidocaine, mepivacaine, pirocaine, bupivacaine, prilocaine, and etidocaine. Examples of cell growth factors include, but are not limited to, epidermal growth factor, human platelet-derived TGF-B, endothelial growth factor, thymocyte-activating factor, platelet-derived growth factor, fibroblast growth factor, fibronectin, or laminin. Examples of lipopolysaccharide complexing agents include, but are not limited to, polymyxin. Examples of peroxides include, but are not limited to, benzoyl peroxide and hydrogen peroxide.

[0056] Examples of antineoplastic agents / anticancer drugs include, but are not limited to, paclitaxel, carboplatin, miconazole, leflunamide, and ciprofloxacin. Examples of antiscarring agents include, but are not limited to, cell cycle inhibitors such as taxanes and immunomodulators such as serolimus or biolimus (see, for example, paras. 64-363, and our U.S. Patent Application Publication No. 2005 / 0149158, which is incorporated herein by reference). Examples of drugs that support ECM integration include, but are not limited to, gentamicin. It is recognized that in certain forms of treatment, combinations of substances / drugs within the same polymer composition can be effective in obtaining optimal effects. Therefore, for example, antibacterial agents and anti-inflammatory agents may be combined in a single copolymer to provide both efficacy. The disclosures herein may be used in connection with injection molded articles, films, non-porous films, drug delivery media, micro / nano drug delivery media, meshes, nonwoven articles, knitted fabrics, woven fabrics, surgical meshes, bioabsorbable stents for internal tubular lumen, 3-D printed materials, drug coatings, temporary implants and their components, and medical supplies formed in situ.

[0057] Unless otherwise explicitly stated, terms and phrases and their variations used herein should be interpreted as unrestrictive, not restrictive, unless otherwise explicitly stated. Similarly, groups of items connected by the conjunction "and" should not be read as requiring each or all of those items to be present in the group, but should be read as "and / or" unless otherwise explicitly stated. Likewise, groups of items connected by the conjunction "or" should not be read as requiring mutual exclusivity between the groups, but should be read as "and / or" unless otherwise explicitly stated. Furthermore, while items, elements, or components of this disclosure may be described or requested in the singular, unless otherwise explicitly stated, the plural is considered to be within their scope. The presence of broad phrases such as “one or more,” “at least,” “but not limited to,” or other similar phrases should not be interpreted as meaning that narrower examples are intended or required in cases where such broad phrases are not necessary. While this subject matter has been described in detail with respect to specific exemplary embodiments and methods thereof, those skilled in the art will understand that, once the above understanding is achieved, modifications, variations, and equivalents of such embodiments can be readily obtained. Therefore, the scope of this disclosure is illustrative and not limiting, and the disclosure of this subject matter can be readily obtained by those skilled in the art using the teachings disclosed herein. This does not exclude such changes, modifications, and / or additions to the subject matter, as is evident therefrom. Another aspect of the present invention may be as follows: [1] A multiaxial core having at least three axes, wherein at least three axes contain polymer chains, and the multiaxial core At least one flexible bonding segment, A polymer end graft comprising repeating units derived from at least one crystalline cyclic monomer, wherein the at least one polymer end graft is attached to each of at least three axes, An absorbent aliphatic polyester copolymer characterized by containing [a specific compound]. [2] The absorbent aliphatic polyester copolymer according to [1], wherein the multiaxial core includes a crystalline polymer chain segment. [3] The absorbable aliphatic polyester copolymer according to [1], wherein the multiaxial core includes amorphous chain segments. [4] The absorbent aliphatic polyester copolymer according to [1], wherein the flexible bond segment and the crystallizable cyclic monomer share a common monomer. [5] The absorbent aliphatic polyester copolymer according to [1], wherein the flexible bond segment is composed of the same prepolymer as the multiaxial core and the same crystallizable cyclic monomer as at least one polymer end graft. [6] The absorbent aliphatic polyester copolymer according to [1], wherein the prepolymer may be a homopolymer, copolymer or terpolymer formed from the group consisting of L,L-lactide, D,L-lactide, glycolide, substituted glycolide, para-dioxanone, 1,5-dioxepant-2-one, trimethylene carbonate, epsilon-caprolactone, alpha-angelicalactone, gamma-valerolactone, and delta-valerolactone, or combinations thereof. [7] The absorbent aliphatic polyester copolymer according to [6], wherein the prepolymer is derived from epsilon-caprolactone, trimethylene carbonate, or a combination of the two thereof. [8] The absorbent aliphatic polyester copolymer according to [1], wherein the prepolymer is derived from glycolide, trimethylene carbonate, or a combination of the two thereof. [9] The absorbent aliphatic polyester copolymer according to [1], wherein the copolymer comprises at least four different blocks, including a central crystallizable core having at least three axes, each containing crystallizable terminal blocks grafted in at least three axes.

[10] The absorbent aliphatic polyester copolymer according to [1], wherein the at least one crystallizable cyclic monomer is selected from the group consisting of L,L-lactide and D,L-lactide, glycolide, substituted glycolide, para-dioxanone, 1,5-dioxepant-2-one, trimethylene carbonate, epsilon-caprolactone, alpha-angelicalactone, gamma-valerolactone and delta-valerolactone, or combinations thereof.

[11] The absorbent aliphatic polyester copolymer according to [1], wherein the flexible binding segment may be derived from trimethylene carbonate, ε-caprolactone, or a combination of the two thereof.

[12] The absorbent aliphatic polyester copolymer according to [1], further comprising an absorbent barrier, web, mesh, or fabric.

[13] The absorbent aliphatic polyester copolymer described in

[12] , wherein the copolymer is formed in a warp-knit mesh.

[14] The absorbent aliphatic polyester copolymer according to [1], further comprising an absorbent polymer surface coating for controlled drug delivery.

[15] A method for producing an absorbent aliphatic polyester copolymer, A step of filling a reactor with monomers, an initiator and a catalyst, wherein the monomer-to-catalyst ratio is at least 25,000. The initiator has at least one hydroxyl group capable of initiating ring-opening polymerization, The monomer comprises at least one cyclic monomer in the process, A step of heating the reactor to at least 100°C, A step of stirring the monomer, initiator and catalyst to form a homogeneous mixture prepolymer, wherein the mass of the prepolymer is greater than 10 kDa, and A process for forming a copolymer having multiple amorphous prepolymer axes and crystalline end grafts extending from each axis. A method characterized by including the following.

[16] The method according to

[15] , wherein the catalyst is stannous octanoate.

[17] The method according to

[15] , wherein the initiator is selected from the group consisting of small molecules, oligomers, polymers, inorganic salts and organic salts having hydroxyl, or combinations thereof.

[18] The method according to

[17] , wherein the initiator is selected from the group consisting of 1-decanol, 1,3-propanediol, trimethylolpropane, triethanolamine, 1,3,4-trihydroxy-2-butanone, glycerol, or a combination thereof.

[19] The method according to

[15] , wherein the monomer is a copolymer or terpolymer derived from lactide, trimethylene carbonate, and / or ε-caprolactone.

[20] The method according to

[15] , wherein the monomer is a copolymer or terpolymer derived from glycolide, trimethylene carbonate and / or ε-caprolactone.

[21] The method according to

[15] , wherein the monomer is a substituted glycolide.

[22] The method according to

[15] , wherein a second packing material of the catalyst is added to the reactor.

[23] The method according to

[15] , wherein two independent temperature settings are established during the reaction.

Claims

1. A thermally stable and absorbent aliphatic polyester copolymer having a delayed onset of thermal decomposition temperature compared to a corresponding aliphatic polyester copolymer prepared at a molar ratio (M / C) of 35,000 of the total amount (M) of a first cyclic monomer and a second cyclic monomer to the total amount (C) of the ring-opening polymerization catalyst, comprising: (1) an amorphous prepolymer forming at least three axes; and (2) crystalline end grafts emanating from each of the amorphous prepolymers. (a) The amorphous prepolymer is selected from homopolymers, copolymers, or terpolymers comprising a first cyclic monomer selected from L,L-lactide, D,L-lactide, glycolide, substituted glycolide, para-dioxanone, 1,5-dioxepant-2-one, trimethylene carbonate, epsilon-caprolactone, alpha-angelicalactone, gamma-valerolactone, and delta-valerolactone, or combinations thereof, and is prepared in the presence of an initiator having multiple alcohol groups and in the presence of the ring-opening polymerization catalyst. (b) The amorphous prepolymer is grafted with a second cyclic monomer selected from L,L-lactide, D,L-lactide, glycolide, substituted glycolide, para-dioxanone, 1,5-dioxepant-2-one, trimethylene carbonate, epsilon-caprolactone, alpha-angelicalactone, gamma-valerolactone, and delta-valerolactone, or a combination thereof, in the presence of the amorphous prepolymer and the ring-opening polymerization catalyst. A thermally stable and absorbent aliphatic polyester copolymer characterized in that the molar ratio of the total amount of the first cyclic monomer and the second cyclic monomer to the total amount of the ring-opening polymerization catalyst is greater than 50,000.

2. A thermally stable and absorbent aliphatic polyester copolymer having a delayed onset of thermal decomposition temperature compared to a corresponding aliphatic polyester copolymer prepared at a molar ratio (M / C) of 35,000 of the total amount (M) of the first cyclic monomer and the second cyclic monomer to the total amount (C) of the ring-opening polymerization catalyst, comprising: (1) a crystalline prepolymer forming at least three axes; and (2) crystalline end grafts emanating from each of the crystalline prepolymers. (a) The crystalline prepolymer is selected from homopolymers, copolymers, or terpolymers comprising a first cyclic monomer selected from L,L-lactide, D,L-lactide, glycolide, substituted glycolide, para-dioxanone, 1,5-dioxepant-2-one, trimethylene carbonate, epsilon-caprolactone, alpha-angelicalactone, gamma-valerolactone, and delta-valerolactone, or combinations thereof, and is prepared in the presence of an initiator having multiple alcohol groups and in the presence of the ring-opening polymerization catalyst. (b) The crystalline prepolymer is grafted with a second cyclic monomer selected from L,L-lactide, D,L-lactide, glycolide, substituted glycolide, para-dioxanone, 1,5-dioxepant-2-one, trimethylene carbonate, epsilon-caprolactone, alpha-angelicalactone, gamma-valerolactone, and delta-valerolactone, or a combination thereof, in the presence of the crystalline prepolymer and the ring-opening polymerization catalyst. A thermally stable and absorbent aliphatic polyester copolymer characterized in that the molar ratio of the total amount of the first cyclic monomer and the second cyclic monomer to the total amount of the ring-opening polymerization catalyst is greater than 50,000.

3. A thermally stable and absorbent aliphatic polyester copolymer having a delayed onset of thermal decomposition temperature compared to a corresponding aliphatic polyester copolymer prepared at a molar ratio (M / C) of 35,000 of the total amount (M) of the first cyclic monomer and the second cyclic monomer to the total amount (C) of the ring-opening polymerization catalyst, comprising: (1) a semi-crystalline aliphatic polyester prepolymer forming at least three axes; (2) crystalline end grafts emanating from each of the semi-crystalline aliphatic polyester prepolymers; and (3) optionally a flexible linker between the semi-crystalline aliphatic polyester prepolymer and the crystalline end grafts. (a) The semicrystalline aliphatic polyester prepolymer is selected from homopolymers, copolymers, or terpolymers comprising a first cyclic monomer selected from glycolide, lactide, para-dioxanone, trimethylene carbonate, and morpholine dione, or combinations thereof, and is prepared in the presence of an initiator having multiple alcohol groups and in the presence of the ring-opening polymerization catalyst. (b) The semicrystalline aliphatic polyester prepolymer is grafted with a second cyclic monomer selected from L,L-lactide, D,L-lactide, glycolide, substituted glycolide, para-dioxanone, 1,5-dioxepant-2-one, trimethylene carbonate, epsilon-caprolactone, alpha-angelicalactone, gamma-valerolactone, and delta-valerolactone, or a combination thereof, in the presence of the semicrystalline aliphatic polyester prepolymer and the ring-opening polymerization catalyst. A thermally stable and absorbent aliphatic polyester copolymer characterized in that the molar ratio of the total amount of the first cyclic monomer and the second cyclic monomer to the total amount of the ring-opening polymerization catalyst is greater than 50,000.

4. The thermally stable and absorbent aliphatic polyester copolymer according to any one of claims 1 to 3, wherein the molar ratio of the total amount of the first cyclic monomer and the second cyclic monomer to the total amount of the ring-opening polymerization catalyst is greater than 100,000.

5. The thermally stable and absorbent aliphatic polyester copolymer according to claim 3, wherein the crystalline terminal graft contains 80 to 90 mol% lactide.

6. The thermally stable and absorbent aliphatic polyester copolymer according to claim 3, wherein the crystalline terminal graft comprises at least 50 mol% of glycolide as a second cyclic monomer.

7. The thermally stable and absorbent aliphatic polyester copolymer according to claim 3, wherein the flexible linker comprises a third cyclic monomer selected from glycolide, lactide, para-dioxanone, epsilon-caprolactone, trimethylene carbonate, and morpholindione, or a combination thereof.

8. The thermally stable and absorbent aliphatic polyester copolymer according to any one of claims 1 to 4, wherein the initiator is selected from trimethylolpropane, triethanolamine, 1,3,4-trihydroxy-2-butanone, and glycerol, or a combination thereof.

9. The ring-opening polymerization catalyst is a first tin octoate, Sn(Oct) 2 , Sn(OTf) 2 , dibutyltin(II)-2-ethylhexanoate (Bu 2 Sn(Oct) 2 A thermally stable and absorbent aliphatic polyester copolymer according to any one of claims 1 to 4, selected from ), and 4-(dimethylamino)pyridine (DMAP).

10. The thermally stable and absorbent aliphatic polyester copolymer according to any one of claims 1 to 4, wherein the crystalline terminal graft comprises at least 50 mol% of glycolide as a second cyclic monomer.

11. The thermally stable and absorbent aliphatic polyester copolymer according to any one of claims 1 to 4, wherein the crystalline terminal graft comprises at least 50 mol% lactide as a second cyclic monomer.

12. The thermally stable and absorbent aliphatic polyester copolymer according to claim 1, wherein the amorphous prepolymer comprises trimethylene carbonate (TMC) as a first cyclic monomer.

13. The thermally stable and absorbent aliphatic polyester copolymer according to claim 2, wherein the crystalline prepolymer comprises trimethylene carbonate as a first cyclic monomer.

14. The thermally stable and absorbent aliphatic polyester copolymer according to claim 1, wherein the amorphous prepolymer comprises trimethylene carbonate and epsilon-caprolactone as the first cyclic monomer.

15. The thermally stable and absorbent aliphatic polyester copolymer according to claim 1, wherein the crystalline terminal graft contains at least 90 mol% glycolide.

16. The thermally stable and absorbent aliphatic polyester copolymer according to claim 2, wherein the crystalline terminal graft contains at least 90 mol% glycolide.

17. The thermally stable and absorbent aliphatic polyester copolymer according to claim 1, wherein the ring-opening polymerization catalyst is a first tin octoate.

18. The thermally stable and absorbent aliphatic polyester copolymer according to claim 1, wherein the amorphous prepolymer has a molecular weight greater than 10 kDa.

19. The thermally stable and absorbent aliphatic polyester copolymer according to claim 1, wherein the amorphous prepolymer has a molecular weight greater than 20 kDa.

20. A fiber characterized by containing a thermally stable and absorbent aliphatic polyester copolymer as described in any one of claims 1 to 19.

21. An absorbent barrier, web, mesh, or fabric characterized by comprising the fibers described in claim 20.

22. A warp-knitted mesh characterized by containing the fibers described in claim 20.

23. An absorbent polymer surface coating for controlled drug delivery, characterized by comprising an aliphatic polyester copolymer as described in any one of claims 1 to 19.

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