Polyester urethane bioabsorbable elastomer with microstructure for adjustable drug release and adjustable degradation.

Abstract

The composition comprises a polyester urethane. The polyester urethane comprises a diisocyanate-based crosslinking agent and an alternating copolymer resin of polyol and polyacid. The resin has a degree of branching, weight-average molecular weight, polydispersity index, and viscosity before crosslinking. The polyester urethane has a microstructure of rigid and flexible segments based on a selected combination of polyol, polyacid monomer, degree of branching, weight-average molecular weight, polydispersity index, viscosity, diisocyanate, a first stoichiometric ratio, and a second stoichiometric ratio. The microstructure provides the composition with predetermined properties selected from the decomposition rate in an aqueous environment, the release rate of a drug supported in the polyester urethane in an aqueous environment, the solubility of the drug, and combinations thereof.

Description

[Technical Field]

[0001] References to related applications

[0001] This application claims priority and interest to U.S. Provisional Applications No. 63 / 515,399, No. 63 / 515,402, and No. 63 / 515,403, all of which were filed on July 25, 2023, and which are incorporated herein by reference in their entirety.

[0002]

[0002] The disclosure generally relates to methods for forming urethane-containing polymers and compositions formed by such methods. More specifically, the disclosure relates to methods for forming polyester urethane (PEU) polymers having adjustable decomposition and controlled release rates and compositions formed by such methods. [Background technology]

[0003]

[0003] Most biodegradable biomaterial polymers used for drug delivery are bulk eroders that exhibit a dose-dependent release rate of active pharmaceutical ingredients (APIs), where increasing the drug-loaded concentration increases the relative release rate. With such polymers, increasing the loading rate also creates a steeper concentration gradient between the polymer matrix and the surrounding environment, making it difficult to achieve high drug loading rates that provide sustained release for longer than three months. Subsequently, release occurs more rapidly. Therefore, for bulk eroders such as poly(lactic acid-coglycolic acid) (PLGA), polyglycolic acid (PGA), polylactic acid (PLA), or polycaprolactone (PCL), when the loading rate is about 40% by weight or less, the release rate is often low enough to achieve controlled release therapy for longer than three months, while loading rates of about 50% by weight or more often exhibit a significantly faster release rate, and therefore, in many cases, only provide controlled release therapy for at most one month.

[0004]

[0004] Since both bulk erosive and non-erosive drug delivery systems are diffusion-driven, this same limitation is observed when using non-degradable polymers such as poly(ethylene-co-vinyl acetate) (EVA), polyurethane (PU), and silicone. This was demonstrated, for example, by Barrett et al. ("Extended Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention," Antimicrob. Agents Chemother., Vol. 62, Issue 10, 2018), where EVA, PCL, and PLA showed a sharp increase in release rate as the drug load increased from 40% by weight to 50%, 60%, and 80% by weight. At a load of 60% by weight, the release duration from all three polymers was only 2 months. At a load of 80% by weight, the release duration decreased to 1 month. Furthermore, bulk erosive polymers often exhibit dose dumping once they reach critical mass loss.

[0005]

[0005] The release rate can depend heavily on the solubility of the API, but it is highly preferable to have a polymer carrier capable of sustainably delivering the API across the solubility distribution for at least three months, and possibly several months. Highly soluble APIs pose a challenge to non-degradable and bulk-eroding polymers because they diffuse rapidly from the polymer matrix, likely resulting in large burst releases and fast release rates. On the other hand, poorly soluble APIs also pose a challenge to non-degradable and bulk-eroding polymers because they do not diffuse easily from the polymer matrix, such as BCS class II (low solubility, high permeability) and BCS class IV (low solubility, low permeability). In particular, it is usually not possible to achieve a sufficient release rate within a reasonable timeframe after transplantation. The majority of new drug entities developed by the pharmaceutical industry are BCS classes II and IV, and therefore, solubility and permeability issues are becoming increasingly important for managing effective controlled drug delivery. However, BCS class I and III APIs are also of great interest for controlled release. Therefore, it is desirable to have polymer delivery systems that can deliver both highly soluble and poorly soluble APIs in the form of a matrix that is essentially indeterminate to what the API is. Furthermore, it is also highly desirable to have polymer delivery systems that release APIs not solely by diffusion, but in combination with diffusion, or by surface erosion alone, or through surface erosion.

[0006]

[0006] Poly(glycerol sebacate)urethane (PGSU) comprises the constituent units glycerol, sebaic acid, and diisocyanate. Specifically, PGSU, composed of glycerol, sebaic acid, and hexamethylene diisocyanate (HDI), is crosslinked with relatively high crosslinking densities, such as isocyanate to hydroxyl stoichiometric ratios of 1:1.25 to 1:0.25. This higher crosslinking imparts many useful properties to PGSU, such as storage stability at room temperature, low extractable and leaching properties, excellent biocompatibility, and mechanical robustness. This composition of PGSU has been very successful in achieving sustained release of various small molecule drugs, or APIs. APIs with various solubility, hydrophilic / hydrophobicity, molecular weight, log(P) value, pKa, particle size and morphology, surface energy, and charge can be delivered from PGSU grafts, and they can provide sustained release for 3 months or longer, and in some cases for as long as 24 months.

[0007]

[0007] Conventional compositions of PGSU include poly(glycerol sebacate) (PGS) soft segments crosslinked with HDI. PGSU degradation occurs after water interacts with ester bonds in the soft segments, causing bond cleavage through hydrolysis, and also, on a much longer and slower timescale, water can interact with urethane bonds in the hard segments, causing hydrolysis, ultimately leading to the dissolution of polymer degradation products. Given how slow and unlikely it is to hydrolyze urethane bonds compared to ester bonds, one way to formulate polyester urethane for faster degradation is to have fewer urethane bonds. Some of the existing strategies used to tune the degradation kinetics of these networks rely on changing the crosslink density or isocyanate-to-polyol ratio. However, altering the crosslink density directly affects the polymer's mesh size, drug release kinetics, storage stability, durability, strength, extractable and leached product profiles, biocompatibility, and surface-to-bulk erosion properties. Another existing strategy involves varying the curing conditions and the length of the diacid copolymerized with erythritol (e.g., Barrett et al., "Aliphatic polyester elastomers derived from erythritol and α,ω-diacids," Polym. Chem., Vol. 1, pp. 296-302 (2010)).

[0008]

[0008] Conventional PGSU compositions contain a soft segment having ester bonds separated by an 8-carbon methylene chain of the sebaciate molecule. Since hydrolysis products, specifically acidic decomposition products, can catalyze adjacent hydrolysis reactions, the cleavage of one ester bond increases the likelihood of cleaving adjacent ester bonds. Equivalent networks with shorter carbon chains between adjacent ester bonds, in other words, networks with a higher ester density or a greater abundance of catalyst products, can increase the hydrolysis rate in the network. Therefore, by designing polymer networks with varying degrees of polyacid-rich domains, networks with tunable hydrolysis rates can be created.

[0009]

[0009] Substituting sebacic acid with shorter polycarboxylic acids to create novel highly branched polyesters having glycerol-polyacid repeating units but with different degradation profiles has been previously described (see, for example, Zhang et al., "Synthesis and characterization of glycerol-adipic acid hyperbranched polyesters," Polymer, Vol. 55, pp. 5065-5072, 2014). Others have also synthesized copolymers of sebacic acid and succinic acid to create branched copolymers containing both polyacids (see, for example, Godinho et al., "Synthesis of Prepolymers of Poly(glycerol-co-diacids) Based on Sebacic and Succinic Acid Mixtures," ACS Omega, Vol. 18, pp. 16194-16205, 2023).

[0010]

[0010] Conventional PGSU having a stoichiometric ratio of isocyanate to hydroxyl of approximately 1:1 to 1.1:1 has a degradation time in the range of 12 to 36 months, depending on the geometry and anatomical location of the device. Recent data on such PGSU indicates that when examined across multiple in vitro and in vivo datasets, depending on the geometry of the construct, it degrades as a non-loaded construct in approximately 2 years and as a 40 - 60% loaded construct in approximately 2 - 3 years. For example, a 40% loaded micro-rod with a diameter of 457 micrometers completely degraded in vitro in 20 - 24 months. In contrast, a 1 mm diameter rod with a 50% loading rate with a highly hydrophobic API maintained its shape after 2.6 years with a twice-weekly media change. Existing conventional compositions of PGSU, despite various solvation, porogen, and dimensional strategies having been attempted, cannot degrade in a shorter time frame without changing the crosslink ratio and without affecting the advantages listed above. Thus, there is a need for various methods to adjust the polymer degradation rate to fit various therapeutic applications without changing the crosslink density. Even conventional PGS resins without any crosslinking do not readily degrade within a time frame that is suitably fast enough for many applications, highlighting the need for an improved polyester resin composition that degrades faster than conventional PGS.

[0011]

[0011] For controlled drug release applications, it is highly desirable to synchronize the drug release kinetics with the polymer degradation kinetics. This avoids the polymer being left in situ after the drug payload has already been depleted. Thus, it is desirable to have polymer compositions that can degrade at a faster rate to fit various drug release rates. More specifically, it is desirable to achieve short polymer degradation lifetimes of about 1 month, 3 months, 6 months, 9 months, 12 months, and up to about 18 months.

[0012]

[0012] Reducing the crosslink density can be one approach to achieve faster degradation, but simply reducing the crosslink density of PGSU by reducing the urethane-polyol ratio or the isocyanate-to-hydroxyl stoichiometric ratio (NCO:OH molar:mol) does not lead to satisfactory performance results. Reducing the isocyanate-to-hydroxyl stoichiometric ratio to less than 1:1.25, for example to 1:2.5, 1:3.5, and 1:4.5, results in a bulk degradation mechanism. Bulk degradation may be unfavorable for sustained release compared to surface erosion due to inconsistent, low linearity, and unpredictable polymer chain severation and drug release. Bulk degradation occurs when water infiltration exceeds the rate of polymer bond hydrolysis. Furthermore, reducing the isocyanate-to-hydroxyl stoichiometric ratio to less than 1:1.25 results in very poor release kinetics. Furthermore, the degradation profile of these less crosslinked PGSU formulations appears to limit solubility due to the low water solubility of sebacic acid (0.25 mg / mL) and the size limitations of PGS oligomers containing glycerol and sebacic acid (insoluble above 1000 Da), which causes slower mass loss than expected, even with lower crosslinking. This is a greater problem for grafts targeting anatomical locations with low liquid volume and low liquid flow conditions, such as ocular or subcutaneous grafts.

[0013]

[0013] When biodegradable polymer grafts decompose, they break down into smaller molecules, oligomers, or fragment biodegradates, which can separate from the bulk polymer, solubilize in the surrounding liquid, and be eliminated from the body. By increasing the solubility of the biodegradates, more suitable biodegradable graftable polymers can be produced, as this allows for more control over the rate and mechanism of decomposition. During hydrolysis, the movement of fragments from the bulk polymer depends on the water solubility of the fragments. If the fragments are water soluble, this gives them mobility to escape and eventually leave the bulk, which provides porosity and causes them to form a more open mesh size and hydrolysis susceptibility in the remaining polymer bulk, thus improving the movement of fragments within the bulk polymer as well. If the fragments have lower solubility in water, they cannot be expelled from the bulk, which can prevent future water infiltration and access, thus slowing the rate of decomposition. If the polymer contains acidic components, the decomposed fragments containing acidic functionality need to be water soluble so that further decomposition is catalyzed by acid. Furthermore, if the fragments are not very soluble in the body's natural aqueous fluids, they will not easily come into contact with enzymes or immune cells that can further break them down. In summary, it is not enough for polymer networks to have cleavable sites; rather, the cleaved fragments need to be excreted, and if the fragments are water-soluble, their excretion is improved.

[0014] Biodegradable urethanes generally decompose via a three-step process involving water diffusion into the polymer, hydrolysis and bond cleavage, and dissolution of the degradation products. Conventional compositions and methods for creating PGSU mainly control the degradation kinetics by varying the ratio of crosslinker to prepolymer, thereby changing the crosslink density of the resulting PGSU. This conventional approach is effective for creating compositions that lose mechanical strength more rapidly, but does not accelerate mass loss sufficiently. Instead, this conventional approach reaches the solubility limit in the dissolution step of the degradation products of polymer degradation. This limits the ability to regulate polymer degradation, especially in therapeutic in vivo applications, when the polymer is not suspended in an excess liquid volume and flow as seen in typical in vitro testing conditions. Furthermore, this has a negative impact on drug release from biodegradable urethanes carrying API because, if the degradation kinetics are too slow, the main mechanism for release switches from surface erosion to diffusion.

[0015]

[0015] Conventional compositions of PGSU decompose to form biodegradable products with low water solubility. Conventional PGSU formulations often have a significant time lag between the loss of mechanical integrity and polymer dissolution, mass loss, and dimensional loss. This time lag can make the overall degradation process less controllable, particularly depending on the liquid flow properties at the anatomical location of the polymer graft, potentially making the device's lifespan and properties unpredictable. Degradable products with better water solubility can be hydrolyzed more easily and rapidly because water can access the molecular structure and hydrolytic cleavage sites of the decomposed products more freely when solubilized. Also, less soluble decomposed products may require more decomposition to become small enough fragments that are water-soluble. Slow biodegradation can be disadvantageous in applications where the material needs to decompose rapidly, such as in biomedical, pharmaceutical, veterinary, cell culture, diagnostics, bioprocessing, cosmetics, personal care, industrial, agricultural, or environmental applications. Poorly soluble degradation products can accumulate in the environment or biological systems, potentially causing toxicity, inflammation, or other adverse effects, and are more likely to trigger inflammation or immune responses. This could limit the usefulness of such polymers in medical applications or other situations where biocompatibility is critical, and they may be more difficult to process and handle during manufacturing or disposal, potentially increasing costs, logistical challenges, and environmental impacts. The generation of poorly soluble degradation products may limit the potential use of biodegradable polymers, particularly in applications where solubility is critical, such as drug delivery or other medical applications. Furthermore, the generation of poorly soluble degradation products may limit the use of polymers in anatomical locations with high levels of liquid and liquid-fluid states, high and low pH, high enzyme concentrations and activity, numerous phagocytic cell types that help remove poorly soluble degradation products, and nearby lymphatic drainage. [Overview of the project] [Problems that the invention aims to solve]

[0016]

[0016] In summary, this indicates the need for a more complex approach to polymer design in order to achieve polyester urethane that degrades more rapidly but still sustains drug release. [Means for solving the problem]

[0017]

[0017] In some embodiments, the composition comprises a polyester urethane. The polyester urethane comprises a diisocyanate-based crosslinking agent and an alternating copolymer resin of at least one polyol monomer and at least one polyacid monomer. The crosslinking agent crosslinks the alternating copolymer resin. The alternating copolymer resin has a degree of branching, weight-average molecular weight, polydispersity index, and viscosity before crosslinking. The polyester urethane has a first stoichiometric ratio of at least one polyol to at least one polyacid. The polyester urethane has a second stoichiometric ratio of isocyanate to hydroxyl. The polyester urethane has a degree of phase-separated microstructure between the rigid segment of the crosslinking agent and the flexible segment of the alternating copolymer resin. Crosslinking stabilizes the degree of phase-separated microstructure. The phase separation fine structure is based on a selected combination of at least one polyol monomer, at least one polyacid monomer, degree of branching, weight-average molecular weight, polydispersity index, viscosity, diisocyanate, first stoichiometric ratio, and second stoichiometric ratio. The phase separation fine structure provides the composition with predetermined properties selected from the group consisting of decomposition rate in an aqueous environment, release rate of the drug supported in the polyester urethane in an aqueous environment, drug solubility, and combinations thereof.

[0018]

[0018] In some embodiments, a method for forming a polyester urethane includes selecting at least one polyol monomer, at least one polyacid monomer, and a diisocyanate. The method also includes combining at least one polyol monomer and an aqueous liquid in a container. The method further includes selecting a first stoichiometric ratio of at least one polyol monomer to at least one polyacid monomer, and adding at least one polyacid monomer to the container in the first stoichiometric ratio. The method further includes removing water from the container and producing an alternating copolymer resin of at least one polyol monomer and at least one polyacid monomer. The alternating copolymer resin has a degree of branching, a weight-average molecular weight, a polydispersity index, and viscosity. The method also includes selecting a second stoichiometric ratio of isocyanate to hydroxyl, and homogeneously combining a fluid blend containing the alternating copolymer resin in the second stoichiometric ratio with a diisocyanate to form a polyester urethane. At least one polyol monomer, at least one polyacid monomer, a diisocyanate, a first stoichiometric ratio, a second stoichiometric ratio, branching degree, weight-average molecular weight, polydispersity index, and viscosity are selected to form a phase separation microstructure between the rigid segment of the crosslinking agent and the flexible segment of the alternating copolymer resin. The phase separation microstructure provides predetermined properties selected from the group consisting of decomposition rate in an aqueous environment, release rate of the drug supported in the polyester urethane in an aqueous environment, drug solubility, and combinations thereof.

[0019]

[0019] In some embodiments, the implantable product comprises a drug and a polyester urethane. The polyester urethane comprises a diisocyanate-based crosslinking agent and an alternating copolymer resin of at least one polyol monomer and at least one polyacid monomer. The crosslinking agent crosslinks the alternating copolymer resin. The alternating copolymer resin has a degree of branching, weight-average molecular weight, polydispersity index, and viscosity before crosslinking. The polyester urethane has a first stoichiometric ratio of at least one polyol to at least one polyacid. The polyester urethane has a second stoichiometric ratio of isocyanate to hydroxyl. The polyester urethane has a phase separation microstructure between the rigid segment of the crosslinking agent and the flexible segment of the alternating copolymer resin. Crosslinking stabilizes the phase separation microstructure. The phase separation microstructure is based on a selected combination of at least one polyol monomer, at least one polyacid monomer, degree of branching, weight-average molecular weight, polydispersity index, viscosity, diisocyanate, first stoichiometric ratio, and second stoichiometric ratio. The phase separation microstructure provides the composition with predetermined properties selected from the group consisting of the decomposition rate in an aqueous environment, the release rate of the drug supported in the polyester urethane in an aqueous environment, the solubility of the drug, and combinations thereof. [Brief explanation of the drawing]

[0020] [Figure 1]

[0020] Figure 1 shows a plot of the conversion rates of glycerol, sebaciic acid, and adipic acid during polycondensation to form poly(glycerol sebacate-co-adipate) with a monomer stoichiometric supply ratio of 1:0.5:0.5. [Figure 2]

[0021] Figure 2 shows the overall evolution of monomers, polymers, and microstructure during polycondensation to form poly(glycerol sebacate-co-adipate). [Figure 3]

[0022] Figure 3 shows a plot of the degree of branching of polyester resin versus the relative molar ratio of 1,2,3-triacylglycerides. [Figure 4]

[0023] Figure 4 shows a plot of the weight-average molecular weight of polyester resin versus the relative molar ratio of 1-acylglycerides. [Figure 5]

[0024] Figure 5 shows a plot of the weight-average molecular weight of polyester resin versus the relative molar ratio of 1,2,3-triacylglyceride. [Figure 6]

[0025] Figure 6 shows a radar plot of polyester urethane having a polyester component formed from polyesters with various molecular weights. [Figure 7]

[0026] Figure 7 shows radar plots of polyesters having a polyol:polyacid molar ratio of either 1:1 or 1.1:1, and PGSU formulations prepared using either HDI or lysine diisocyanate ethyl ester (LDI). [Figure 8]

[0027] Figure 8 shows radar plots of PGSU formulations prepared using polyesters with a polyol:polyacid molar ratio of either 1:1 or 1.1:1, and prepared using HDI. [Figure 9]

[0028] Figure 9 shows radar plots of PGSU formulations prepared using polyesters with a polyol:polyacid molar ratio of either 1:1 or 1.1:1, and using LDI. [Figure 10]

[0029] Figure 10 shows radar plots of PPGSU formulations prepared using polyesters containing sebacic acid and either adipic acid or succinic acid, and using HDI. [Figure 11]

[0030] Figure 11 shows radar plots of PGSU formulations prepared using a polyester containing either adipic acid or a polyacid copolymer of adipic acid and sebaciate in a molar ratio of 50:50 or 25:75, and prepared using HDI. [Figure 12]

[0031] Figure 12 shows radar plots of PGSU formulations prepared using polyesters containing either adipic acid or sebacic acid in a polyol:polyacid molar ratio of 1:1 or 1.1:1, and prepared using HDI. [Figure 13]

[0032] Figure 13 shows the decomposition time versus molecular weight of HDI crosslinked polyester urethane at 70°C. [Figure 14]

[0033] Figure 14 shows the decomposition time versus molecular weight of LDI crosslinked polyester urethane at 70°C. [Figure 15]

[0034] Figure 15 shows the degradation percentage versus crosslink density for LDI crosslinked polyester urethane after 4 weeks at 70°C. [Figure 16]

[0035] Figure 16 shows the degradation percentage versus crosslink density after 4 weeks at 70°C for free acid-doped polyester urethane. [Figure 17]

[0036] Figure 17 shows the degradation percentage versus crosslink density for HDI crosslinked polyester urethane after 4 weeks at 70°C. [Figure 18]

[0037] Figure 18 shows the degradation percentage versus crosslink density after 4 weeks at 70°C for polyester urethane using a crosslinking agent mixture. [Figure 19]

[0038] Figure 19 shows the sol content for a particular polyester urethane. [Figure 20]

[0039] Figure 20A shows the mass loss results for the selected group of polyester urethane grafts.

[0040] Figure 20B shows the results of the diameter loss for the polyester urethane grafts in Figure 20A. [Figure 21]

[0041] Figure 21 shows the degradation profile of the polyester urethane graft. [Figure 22]

[0042] Figure 22 shows the further degradation profile of the polyester urethane graft. [Figure 23]

[0043] Figure 23 shows the swelling of the selected polyester urethane in tetrahydrofuran (THF). [Figure 24]

[0044] Figure 24 shows further swelling of polyester urethane in THF. [Figure 25]

[0045] Figure 25 shows the swelling of the selected polyester urethane in water. [Figure 26]

[0046] Figure 26 shows the swelling in water for further selected polyester urethanes. [Figure 27]

[0047] Figure 27 shows water uptake for further selected polyester urethane. [Figure 28]

[0048] Figure 28 shows the crosslinking densities of various polyester urethanes. [Figure 29]

[0049] Figure 29 shows the crosslinking density of a specific family of polyester urethanes. [Figure 30]

[0050] Figure 30A shows the SEM image of the first polyester urethane graft before the 3-month degradation study.

[0051] Figure 30B shows an SEM image of the polyester urethane graft from Figure 30A after a 3-month degradation study and drying by freeze-drying. [Figure 31]

[0052] Figure 31A shows the SEM image of the second polyester urethane graft before the 3-month degradation study.

[0053] Figure 31B shows an SEM image of the polyester urethane grafts from Figure 31A after a 3-month degradation study and drying by freeze-drying. [Figure 32]

[0054] Figure 32 shows the cumulative release profile for a first set of polyester urethane microdevices supported with 60% by weight of dexamethasone. [Figure 33]

[0055] Figure 33 shows the cumulative release profile of a second set of polyester urethane microdevices supported with 60% by weight of dexamethasone. [Figure 34]

[0056] Figure 34 shows the cumulative release profile of a third set of polyester urethane microdevices supported with 60% by weight of dexamethasone. [Modes for carrying out the invention]

[0021]

[0057] This specification provides polymer compositions comprising polyester urethane having a microstructure of generally amorphous polyester soft segments and urethane crosslinked rigid segments, selected to provide the polymer composition with predetermined properties. Also disclosed herein are synthesis and compounding methods for altering the polyester urethane microstructure independently of the crosslink density, which may affect drug release and polymer degradation behavior. The microstructures of the soft and rigid segments are selected individually and collectively with respect to predetermined properties of the resulting polyester urethane composition, based on recognition of their contributions.

[0022]

[0058] In exemplary embodiments, crosslinking captures the microstructure of the polyester soft segments of the polyester urethane and the rigid segments of the urethane crosslinking, providing decomposition and / or release properties. In exemplary embodiments, the decomposition and / or release properties differ from those achieved by conventional PGSU.

[0023]

[0059] In some embodiments, the crosslinking density of the polyester urethane is adjusted by changing the ratio of soft segment polyol to hard segment urethane, thereby adjusting the mechanical properties, release dynamics, and decomposition dynamics.

[0024]

[0060] In some embodiments, the polyester urethane comprises a diisocyanate-based crosslinking agent and an alternating copolymer resin of at least one polyol monomer and at least one polyacid monomer. The crosslinking agent crosslinks the alternating copolymer resin. The alternating copolymer resin has a degree of branching, weight-average molecular weight, polydispersity index, and viscosity before crosslinking. The polyester urethane has a first stoichiometric ratio of at least one polyol to at least one polyacid. The polyester urethane has a second stoichiometric ratio of isocyanate to hydroxyl. The polyester urethane has a phase separation microstructure between the rigid segment of the crosslinking agent and the flexible segment of the alternating copolymer resin. Crosslinking stabilizes the phase separation microstructure. The phase separation microstructure is based on a selected combination of at least one polyol monomer, at least one polyacid monomer, degree of branching, weight-average molecular weight, polydispersity index, viscosity, diisocyanate, the first stoichiometric ratio, and the second stoichiometric ratio. The phase separation microstructure provides predetermined properties selected from the group consisting of the decomposition rate in an aqueous environment, the release rate of the drug supported in the polyester urethane in an aqueous environment, Δlog(P) between the soft segment and the drug, Δlog(P) between the soft segment and the hard segment, Δlog(P) between the drug and the hard segment, the solubility of the drug, and combinations thereof.

[0025]

[0061] Here, the microstructure can be defined at least at two levels. One level is the microstructure of the polyester itself, which is 13This can be determined by 13C NMR, which describes the branching, terminal groups, pendant functional groups, esterification location and frequency, the ratio of these species, and the overall structure of the polyester. For example, as schematically shown below for glycerol (where "P" represents a polymer chain), if the polyol is a triol such as glycerol and the polyacid is a diacid, various degrees of branching can occur depending on which alcohol group forms an ester bond with the carboxylic acid. If there are two free alcohol groups, glycerol is a 1-acylglyceride (1T) as shown in formula (1), or a 2-acylglyceride (2T) as shown in formula (2). If there is one free alcohol group, glycerol is a 1,3-diacylglyceride (1,3L) as shown in formula (3), or a 1,2-diacylglyceride (1,2L) as shown in formula (4). If free alcohol groups are absent, glycerol is a 1,2,3-triacylglyceride (1,2,3D) as shown in formula (5).

[0026] [ka]

[0027]

[0062] As used herein, the degree of branching is defined by equation (1): Branching degree=2(1,2,3D) / (2(1,2,3D)+1,2L+1,3L) (1)

[0063] In some embodiments, the degree of branching is selected to provide the polyester urethane with a predetermined set of properties. A decrease in branching in the polyester structure tends to increase the crystallinity of the matrix, which leads to a higher melting point (Tm). This is one of many features that can be tuned to provide the polyester urethane with a predetermined set of properties. The incorporation of short-chain diacides increases the number of ester bonds, and a given weight-average molecular weight (M) wThis increases the hydroxyl value and therefore affects the crystallinity and hydrophilicity of the matrix. Also, shorter diacitors significantly increase the hydroxyl value and therefore contain more crosslinking agents, thereby increasing the crosslinking density. Surprisingly, despite the higher crosslinking density of matrices with short-chain diacitors, the degradation rate was significantly higher than that with longer-chain diacitors.

[0028]

[0064] The second level concerns how the polyester soft segments are positioned relative to the urethane crosslinked rigid segments. This second polymer microstructure arrangement, particularly the degree of phase mixing, or segment mixing, between the polyurethane rigid and soft segments, has been shown to allow for increased hydrolysis while sustaining or further improving the release dynamics of the hydrophobic API. The degree of phase mixing depends on the intermolecular interactions and thermodynamic stability of the soft and rigid segments.

[0029]

[0065] The arrangement of soft and hard segments may include regions of soft segments only, regions of segment mixing, and / or regions of segment separation within the polyurethane polymer structure. Hard domains containing urethane crosslinks can separate or mix with polyester-containing hard / soft segments based on the thermodynamic and chemical properties of the hard / soft segments. Aggregation of separate hard / soft domains resulting in phase separation may result in distinct drug release / degradation properties within different segments. Furthermore, the overall microstructure and morphology of the polyester urethane may also depend on the interaction between larger aggregated hard domains and the hard segment domains. The presence, quantity, and properties of APIs may also influence the arrangement of hard and hard segment domains.

[0030]

[0066] The microstructure arrangement of rigid and flexible segments in polyester urethane may be determined by one or more methods, including, but not limited to, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), nanospectroscopy, or infrared nanospectroscopy such as atomic force microscopy infrared (AFM-IR) spectroscopy. The microstructure arrangement of drug particles in the polymer phase, such as drug particle dispersion and distribution, may be determined by one or more methods, including, but not limited to, X-ray microscopy (XRM), such as micro-CT or nano-CT, scanning electron microscopy (SEM), mosaic field of view (FOV) SEM, or energy-dispersive X-ray analysis (EDX).

[0031]

[0067] In some embodiments, the chemistry and arrangement of the microstructure are selected to obtain a desired drug release profile decoupled from the polymer erosion profile via a diffusion-based release mechanism.

[0032]

[0068] In some embodiments, the chemistry and arrangement of the microstructure are selected to obtain a desired drug release profile that is decoupled from the polymer erosion profile via a non-covalent interaction-based release mechanism.

[0033]

[0069] In some embodiments, the chemistry and arrangement of the microstructure are selected to obtain a desired drug release profile that is decoupled from the polymer erosion profile via the dispersion and distribution of drug particles.

[0034]

[0070] In some embodiments, the microstructure of the polyester resin is selected based on the selection of polyols, polyacids, and the stoichiometric ratio of polyols to polyacids. In some embodiments, the polyester includes a chain extender. Apart from the chemistry of the polyester resin and crosslinking agent that imparts solubility to the decomposition product fragments, chain extenders and other additives may be used not only to impart hydrolysis-prone bonds but also to impart chemical functional groups that promote interaction in water and higher solubility. Chain extenders and additives added to the polyester resin or during the compounding step may contain hydrophilic functional groups that impart higher water solubility to the soft segment decomposition products upon hydrolysis. In some embodiments, the reaction conditions for forming and processing the polyester are also selected to achieve a predetermined microstructure of the polyester, such as a predetermined weight-average molecular weight, number-average molecular weight, polydispersity, degree of branching, ratio of glyceride species and microstructure, ratio of acid species and microstructure, acid value, hydroxyl value, free acid monomer, or free polyol monomer.

[0035]

[0071] The ester bond spacing on polyester resins remains fixedly unaffected by urethane crosslinking. When the polyol is glycerol (G), the ester bond spacing is a statistically average value, and the spacing is contributed to by glycerol (where two primary hydroxyl groups and one secondary hydroxyl group can form ester crosslinks) and polyacid (where at least two carboxylic acids can form ester crosslinks). Sebacic acid (Seb) has a hydrocarbon (CH2) length of 8, while adipic acid (Ad) has a hydrocarbon length of 4, and succinic acid (Suc) has a hydrocarbon length of 2. Copolymers of these different diacids have combinations of hydrocarbon lengths, which can be molar-averaged across the bulk material. For example, Ad:Seb 50:50 mol% has an average hydrocarbon length of 6, and Suc:Seb 50:50 mol% has an average hydrocarbon length of 5. The ester bond spacing is influenced by how glycerol and polyacid combine during synthesis, how the polymer chain is constructed over time, and which hydroxyl groups on the glycerol are involved in esterification. The tendency of two primary hydroxyl groups of glycerol versus one secondary hydroxyl group to be involved in ester bond formation can differ during synthesis using different diacids. This results in more or less branching, where the branching point is determined by the glycerol having each of the three hydroxyls that form the ester bond.

[0036]

[0072] In some embodiments, the composition comprises a polyester urethane that decomposes in an aqueous environment into decomposition products having a molecular weight greater than 1000 Da, which are soluble in an aqueous environment. The polyester urethane itself is insoluble in an aqueous environment. In some embodiments, the polyester urethane comprises a chemical composition and / or chemical structure selected to form biodegradable products having higher solubility in an aqueous environment than conventional PGSU.

[0037]

[0073] In some embodiments, the reference aqueous environment for determining the solubility of polyester urethane degradation products, or for comparing the solubility of two or more polyester urethane degradation products, is 0.1 M phosphate-buffered saline (PBS) at pH 7.4 and 37°C. In other embodiments, the reference aqueous environment may be 0.1 M PBS at pH 7.4 and 70°C. In other embodiments, the reference aqueous environment may be 0.01 M PBS at pH 7.4 and 37°C, 0.9 wt% sodium chloride (saline) at 37°C, simulated gastric juice (SGF) at pH 1.2, 1.8, or 5.5 and 37°C, or water at 37°C.

[0038]

[0074] In exemplary embodiments, polyester urethane crosslinkers, additives, and / or polyester resins are selected to form polymer degradation products with predetermined solubility, enabling controllable degradation kinetics. The effects of these components, individually and in combination, on the solubility of polymer degradation products provide surprising and unexpected polymer properties. Creating more biodegradable polyurethanes has conventionally involved reducing the crosslink density by reducing the isocyanate-to-hydroxyl stoichiometric ratio, which can result in reduced shelf life, decreased mechanical integrity, worsened sustained drug release, more extractables and leaching materials, higher unreacted sol content, and / or greater blooming of unreacted oligomers. Another conventional approach to forming faster-degrading biomaterials is to reduce the molecular weight, which can result in decreased thermal stability, decreased mechanical integrity, worsened sustained release, and / or greater blooming of mobile oligomers. In some embodiments, the polyester urethane contains degradation products with increased solubility without a reduction in crosslink density and / or molecular weight.

[0039]

[0075] In some embodiments, a polyester urethane polymer network having amphiphilic properties is created, containing both hydrophilic and hydrophobic components. Thus, these polymers can possess the advantages of hydrophobic polymers, such as sustained drug release, surface erosion, and / or viscoelastic properties, while simultaneously overcoming solubility problems during degradation. For example, the increased solubility observed in degradation products of some larger molecular weights greater than 1000 Da appears not simply a result of the solubility of the hydrophilic component, but also a result of some smaller, soluble amphiphilic fragments being able to solubilize larger fragments that would otherwise be insoluble at such high molecular weights. In some embodiments, careful selection of the polymer network can lead to the generation of soluble and solubilizable fragments during biodegradation, which may help induce the solubilization of even larger molecules that are not independently soluble. While we do not wish to be constrained by theory, this may be due to entanglement and / or other non-covalent interactions between many smaller, more hydrophilic fragments and larger chains, which may aid in the solubilization of larger molecules. In some embodiments, the more soluble polyester urethane networks described herein have fragment solubility of up to 120 repeating unit lengths (see Example 21). This 30-fold increase may not be solely attributable to the solubility of simple components or the addition of functional groups, but also to non-trivial interactions between new, smaller amphiphilic fragments and larger, insoluble fragments of the network. This effect is also a result of polydispersion of polyester prepolymer resins synthesized using water-mediated processes, such as those described in U.S. Patent No. 9,359,472, thereby enabling a more significant solubilization effect. Some resin formulations have high proportions of lower molecular weight species, as well as unreacted monomers, that are involved in the solubilization of the mixture. In some embodiments, the resulting polymer network includes hydrophobic soft segments (PGS-LDI) covalently bonded to hydrophilic rigid segments, or vice versa, if shorter polyacids are incorporated.In both cases, the degradation products are amphiphilic molecules that dissolve more readily in the adjacent aqueous environment with a higher molecular weight / lower degree of degradation, resulting in more controlled polymer erosion and degradation.

[0040]

[0076] In some embodiments, a polyester urethane bioabsorbable elastomer having a decomposition product with enhanced solubility is formed using a polyester resin formed by a water-mediated polycondensation process having a polyol:polyacid molar ratio in the range of 0.9:1 to 1.4:1. The polyol and polyacid may be added simultaneously or in stages. Various reaction temperatures, times, and vacuum conditions may be used. Suitable levels of free polyacid and free polyol monomer may be less than about 3% by weight each, less than about 2% by weight each, or any value, range, or partial range between these. Suitable acid values ​​for the polyester resin may be less than about 75 mgKOH / g, less than about 60 mgKOH / g, less than about 50 mgKOH / g, or greater than about 35 mgKOH / g, or any value, range, or partial range between these. Suitable hydroxyl values ​​for polyester resins may include, but are not limited to, values, ranges, or subranges of approximately 240 mgKOH / g or less, approximately 220 mgKOH / g or less, approximately 210 mgKOH / g or more, approximately 180 mgKOH / g or more, or any value, range, or subrange between these.

[0041]

[0077] For reference, copolymers of glycerol and sebacic acid alone with repeating unit lengths of four or fewer, corresponding to a molecular weight of less than approximately 1000 Da, are generally soluble in aqueous environments. Larger oligomers of glycerol-sebacic acid with a molecular weight exceeding approximately 1000 Da are generally not water-soluble. Decomposition products of conventional PGSU, which may contain forms of HDI crosslinkers with a molecular weight exceeding approximately 1000 Da, are also insoluble in aqueous environments.

[0042]

[0078] In some embodiments, the polyester urethane bioabsorbable elastomer composition is formed with a predetermined average ester bond spacing. In some embodiments, the polyester urethane bioabsorbable elastomer composition is formed using a predetermined hydrolysis rate while simultaneously having an isocyanate-to-hydroxyl stoichiometric ratio that remains in the range of approximately 1:1 to 1.1:1. In other embodiments, the isocyanate-to-hydroxyl stoichiometric ratio is in the range of 1:5 to 1:0.25, or 1:1.25 to 1:0.25, or 1:1 to 1.1:1, or any value, range, or subrange between these. In some embodiments, the composition contains components or starting components that can produce a polymer network with a significantly higher hydrolysis rate than that of conventional PGSU. In some embodiments, the combination of components alters the hydrolysis rate in an unexpected non-additive manner. In some embodiments, the resulting polyester urethane bioabsorbable elastomer can be hydrolyzed to low molecular weight biodegradable fragments on a faster timescale than conventional PGSU.

[0043]

[0079] Prepolymers of polyester resins before crosslinking were evaluated by examining a range of properties important for downstream processing into pharmaceuticals and medical devices, including weight-average molecular weight, number-average molecular weight, polydispersity, degree of branching, ratio and microstructure of glyceride species, ratio and microstructure of acid species, acid value, hydroxyl value, free polyacid monomers, free polyol monomers, residual water content, radius of inertia, hydrodynamic radius, glass transition temperature, melting temperature, crystallization temperature, viscosity, refractive index increment, miscibility with diisocyanates, miscibility with other prepolymers, and mixability with drug substances.

[0044]

[0080] The polyol component significantly influences the functional, mechanical, and decomposition behavior of crosslinked polyester urethanes. Suitable polyols may include, but are not limited to, glycerol, ethylenediol, propylenediol, 1,4-butanediol, 1,5-pentanediol, hexanediol, heptanediol, octanediol, nonanediol, 1,10-decanediol, triethylene glycol, xylitol, poly(ethylene glycol), poly(orthoester), or combinations thereof.

[0045]

[0081] Specifically, using a diol instead of a triol as the polyol can result in a more linear polyester resin because the reaction is restricted to terminal hydroxyl groups. Alternatively, polyols with further functionalities can be used to alter the functional, mechanical, and decomposition behavior of crosslinked polyester urethanes. For example, changing the polyol component from glycerol to a polyol with more than three hydroxyl groups, such as xylitol with five hydroxyl groups, can result in a more highly branched polyester resin structure.

[0046]

[0082] The polyacid component of polyester resins significantly affects the functional, mechanical, and decomposition behavior of crosslinked polyester urethanes. More generally, the behavior of crosslinked polyester urethanes can also be altered by changing linear polyacids to polyacids with further functional properties. Suitable linear polyacids include, but are not limited to, sebacic acid, suberic acid, adipic acid, succinic acid, itaconic acid, pimelic acid, or combinations thereof. Suitable non-linear polyacids include, but are not limited to, citric acid. Other suitable monomers include, but are not limited to, acetic acid, glycolic acid, lactic acid, or combinations thereof.

[0047]

[0083] In some embodiments, the polyacid is sebacic acid, forming a more hydrophobic network that can better retain hydrophobic APIs and sustain their release. In other embodiments, the polyacid is less hydrophobic than sebacic acid, forming a less hydrophobic network that provides intermolecular interactions with more hydrophilic APIs and sustains their release. For example, if the drug is dexamethasone, the release rate differs significantly between cases where the polyol is sebacic acid and cases where the polyol is adipic acid. Therefore, polyester compositions can be used to modulate the release of various APIs having varying degrees of hydrophilicity / hydrophobicity.

[0048]

[0084] In some embodiments, an increased frequency of ester bonds based on shorter polyacid segments allows for faster degradation due to a higher density of hydrolysis sites in a given volume. Suitable shorter polyacids may include, but are not limited to, suberic acid, pimelic acid, adipic acid, glutaric acid, succinic acid, oxalic acid, itaconic acid, fumaric acid, maleic acid, or diglycolic acid. In some embodiments, the resulting polyester urethane network includes soft segments having varying inter-ester lengths that control the rate of hydrolysis and overall degradation without changing the soft-segment to hard-segment ratio. In some embodiments, increased solubility of by-product degradation products based on shorter polyacid segments allows for faster degradation because the degradation products are more readily solubilized in an aqueous environment and can more easily detach from the polymer construct network. In some embodiments, increased solubility of by-product degradation products based on specific isocyanates allows for faster degradation because the degradation products are more readily solubilized in an aqueous environment and can more easily detach from the polymer construct network. These polymers can degrade rapidly, within about three months, or slowly, within about three years. In all cases, it is preferable that the degradation products are small enough to be readily removed by the body in vivo.

[0049]

[0085] Depending on the polycondensation reaction conditions, various polyacids are incorporated at various rates, resulting in polyester resins with various microstructures. Using shorter polyacids results in significantly faster reaction kinetics during polymer resin synthesis, which is often more difficult to control using conventional polycondensation reactions. This is an even more significant issue in copolymers where more than one polyacid is involved. If shorter polyacids react with glycerol much faster than longer polyacids, the resulting copolymer has a distorted monomer distribution and an uncontrollable ratio. In other cases, longer polyacids react more completely with glycerol than shorter polyacids, possibly due to chain flexibility. Shorter polyacids are also more water-soluble and more hydrophilic, altering their reaction kinetics during polycondensation, especially when using water-mediated polycondensation processes. A water-mediated synthesis process similar to the one disclosed in U.S. Patent No. 9,359,472 incorporated both sebacic acid and adipic acid well and at similar rates, while succinic acid was not incorporated as efficiently. This was a surprising result, considering that the literature shows the opposite trend for non-aqueous synthesis. These results are related to the microstructure. 1 H-NMR and 13 This was confirmed by 13C-NMR analysis, glyceride species distribution, residual monomer content, degree of polymerization, and degree of diacid incorporation (see, e.g., Examples 3 and 4). Residual monomer content was further confirmed using gel permeation chromatography (GPC) with a refractive index (RI) detector, although gas chromatography-mass spectrometry (GC-MS) may be used as an alternative or further technique for the quantification of residual monomers. Adipic acid-sebacic acid copolymers are likely to have a different chain structure from succinic acid-sebacic acid copolymers, considering the differences in their incorporation rates throughout the polycondensation process, and also considering the differences in their residual monomers after the polycondensation is complete.

[0050]

[0086] How the polyacid and polyol components react to the polyester network constructed during polycondensation is likely to have a significant impact on the resulting microstructure, free pendant functional groups, background functional groups, chain-end functional groups, unreacted free monomers, and extractable and leached materials. For example, water-mediated synthesis of PGS using a higher ratio of glycerol to sebacic acid reduces the number of 1,2,3-triacylglyceride units in the PGS polymer, thereby resulting in a less branched polymer.

[0051]

[0087] In some embodiments, the flexibility of the soft segment polymer chain based on the long polyacid component of the soft segment improves sustained drug release. The long polyacid component of the present invention has a carbon chain length of 8 or longer. For example, the use of sebacic acid having 8 carbon atoms and a linear structure improved the sustained release of dexamethasone more than adipic acid or succinic acid having 4 and 2 carbon atoms, respectively, and also having a linear structure. The long aliphatic chain skeleton of sebacic acid gave it greater chain flexibility compared to shorter polyacids such as adipic acid and succinic acid. Due to its chain length, sebacic acid may be able to coil or condense more freely, thereby allowing the drug to be captured.

[0052]

[0088] Various functional groups can be introduced into polyester resins via selected polyols or polyacids, or via added chain extenders that result in separation from rigid segments during crosslinking, creating separate crystalline regions due to intermolecular interactions between the flexible segment polymer chains. For example, M wA poly(glycerol sebacate) resin having approximately 5,000 glycerol and a glycerol-to-sebacate molar ratio of approximately 1.1:1, crosslinked with HDI and supported with 60 wt% dexamethasone, exhibits significant separation between soft and hard segments. Alternatively, these interactions can be disrupted and attenuated by introducing chemical moieties that preferentially interact with the hard segments, resulting in a phase-mixed microstructure with increased amorphous properties. Furthermore, during the polyurethane compounding and crosslinking process, careful selection of crosslinking agent chemistry can result in fragmented or phase-separated hydrophobic hard segment regions, or increase their interaction with or phase mixing with the soft segments.

[0053]

[0089] In some embodiments, the frequency of free, unbonded pendant hydroxyl groups, based on shorter polyacid segments in the polyester resin, allows for more non-covalent interactions with drugs. In some embodiments, the frequency of ester bonds in the polymer backbone, based on shorter polyacid segments, allows for more non-covalent interactions with drugs. The length of the diisocyanate segment also plays a role in the frequency of ester bonds. Diisocyanates may also contain free, unbonded pendant functional groups in their backbone.

[0054]

[0090] In some embodiments, the frequency of amide or urethane bonds in polymers based on shorter polyacid segments allows for more non-covalent interactions with drugs. The length of the diisocyanate segments also plays a role in the frequency of amide or urethane bonds.

[0055]

[0091] In some embodiments, a higher frequency of terminal groups based on lower molecular weight chains allows for more non-covalent interactions with drugs. The terminal groups may be present in the polyester resin structure and persist after urethane crosslinking. Alternatively, they may appear upon biodegradation of the polyester urethane. In some embodiments, the functionality of the terminal groups, whether hydroxyl or carboxylic acid, contributes to non-covalent interactions with drugs. Diamines generated from the biodegradation of diisocyanates also contribute as terminal groups. In the case of LDI, biodegradation reveals lysine amino acids containing alpha-amino groups, alpha-carboxylic acid groups, and lysyl side chains. In the case of hexamethylene diisocyanates, biodegradation reveals hexamethylenediamines.

[0056]

[0092] Not only the frequency of these functional groups within the polymer network, but also their spatial arrangement is important. The spatial arrangement is determined by the molecular weight and branching of the polymer chains, first in the polyester resin structure resulting from polycondensation (reaction of OH groups with COOH groups), and then in the network structure resulting from urethane crosslinking (reaction of OH groups with CO groups).

[0057]

[0093] Another adjustable parameter is how the hydroxyl groups of the polyol react either during polycondensation, where they react with carboxylic acid groups to form ester bonds, or during urethane crosslinking, where they react with isocyanate groups to form urethane bonds. This highlights the importance of understanding and quantifying the hydroxyl value of polyester resins, whether they are pendants on the skeleton or free hydroxyl groups present at the chain ends. Furthermore, it is important to understand and quantify the available primary and secondary hydroxyls versus the reacted primary and secondary hydroxyls in the polyester resin. For example, a large number of secondary hydroxyls that remain unreacted during polycondensation (not converted to ester crosslinking by polyacids) are subsequently available for urethane crosslinking (converted to urethane crosslinking by diisocyanates). More linear polyesters with low branching and correspondingly low 1,2,3-triglyceride content, e.g., less than 15 mol% 1,2,3-triglycerides, are good examples of this (see, for example, Examples 3 and 4). In this case, more unreacted secondary hydroxyls are present at the completion of polycondensation, and esterification more often occurs at the chain ends, extending the linear portion. This can result in a polymer network with ester bonds mainly along the skeletal chain length and urethane bonds as branching points mainly orthogonal to the chain skeleton. These structural differences affect drug release, water interactions, and polymer degradation products.

[0058]

[0094] Generally, polymer microstructures can be modified to enhance or reduce non-covalent interactions between the polymer backbone, polymer chain ends, and / or polymer pendant functional groups and the drug. Examples of non-covalent interactions include electrostatic interactions, hydrophobic interactions, hydrogen bonding, π-π stacking, and dipole interactions. Hydrophobic interactions and hydrogen bonding are recognized as the most relevant of these non-covalent behaviors for drug-supported polyesterurethanes.

[0059]

[0095] For example, dexamethasone contains a fluorine atom, which is hydrophobic, polar, highly electronegative, and has a high electron density. The electronegativity of fluorine is 3.98. Electronegativity describes an atom's ability to attract another atom and share an electron pair with it. The electronegativity of fluorine on dexamethasone makes it likely to interact with nearby polymer chain functional groups such as pendant hydroxyls, chain-terminal hydroxyls, chain-terminal carboxylic acids, skeletal esters, skeletal polyacid hydrocarbon chains, skeletal diisocyanate hydrocarbon chains, skeletal urethanes or amides, and biodegraded amines. Fluorinated compounds also possess polar hydrophobicity. The polar hydrophobicity of fluorinated dexamethasone makes it likely to interact with nearby polymer chain functional groups such as pendant hydroxyls, chain-terminal hydroxyls, chain-terminal carboxylic acids, skeletal esters, skeletal polyacid hydrocarbon chains, skeletal diisocyanate hydrocarbon chains, skeletal urethanes or amides, and biodegraded amines. Dexamethasone is likely to be involved in dipole interactions, hydrogen bonding, and hydrophobic interactions with soft and / or hard segments. Furthermore, steroid nuclei present in many corticosteroids, including but not limited to dexamethasone, dexamethasone acetate, prednisolone, hydrocortisone, or betamethasone, have been shown to have an affinity for acyl groups within the polymer backbone or pendant groups. This affinity between the acyl-based chemical structure within the polymer and the steroid nuclei of the corticosteroid can be utilized to improve the retention of such APIs within crosslinked polyester urethane polymer networks.

[0060]

[0096] Other functional groups may also be introduced in components incorporated during polycondensation reactions, in post-synthesis functionalization, in components incorporated during the mixing step in urethane crosslinking, or in post-crosslinking functionalization to achieve desired interactions with specific drugs. Functional groups may be incorporated into the soft segment skeleton, the hard segment skeleton, the soft segment pendant groups, or the soft segment chain ends. Suitable components to be included in polycondensation reactions to introduce new functionalities include, but are not limited to, itaconic acid, amine-containing compounds, methacrylates, or acrylates. Suitable post-synthesis functionalization may include, but are not limited to, click chemistry, acetylation of hydroxyl groups, or tethering off the polyester from the hydroxyl pendant to produce block copolymers using ring-opening polymerization of cyclic lactones and thiolactones. Acetylation of the hydroxyl pendant can be controlled to increase the lipophilicity or hydrophobicity of the soft segment, allow for a reduction in the hydroxyl value, and alter the crosslinking density. Acetylated soft segments can be blended with unacetylated soft segments and then mixed with a crosslinking agent.

[0061]

[0097] Suitable additives for incorporation during the mixing step in urethane crosslinking include, but are not limited to, PCL, PLGA, polyethylene glycol (PEG), amine-containing compounds, maleimides, monofunctional isocyanates, or monofunctional isocyanates with other terminal functionalities. Suitable post-crosslinking functionalizations for introducing new functionalities include, but are not limited to, methacrylates, acrylates, cationic charges, anionic charges, PEGs, primary, secondary, or tertiary amine groups, or alkyl chains. Post-crosslinking bioconjugation chemistry schemes, including, but not limited to, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / N-hydroxysuccinimide (EDC / NHS), carbonyldiimidazole CDI, avidin-biotin, streptavidin-biotin, or click chemistry, may be applied to any available residual free functional groups in the polyester urethane.

[0062]

[0098] In particular, monofunctional isocyanates are useful because their single-terminal NCOs contribute to the overall isocyanate-to-hydroxyl stoichiometric ratio, but they do not form double side-chain bridges or crosslinks in the network. Instead, they form single-terminal cantilevers or dangling ends, where the other end is freely involved in a different way. This results in a less crosslinked network overall, but at the same time, the free ends may contain functional groups designed to have a specific affinity for certain drugs. For example, monofunctional isocyanates with aliphatic chains or fatty acid tails may favorably interact with and exhibit affinity for hydrophobic drugs such as dexamethasone. Alternatively, monofunctional isocyanates with pendant unsaturated aromatic rings, saturated six-membered carbon rings, or other bulky functional groups may be used to disrupt the packing or stacking of polymer networks, or otherwise alter their spatial arrangement. Alternatively, monofunctional isocyanates with hydrophilic pendant functional groups may be used to improve water uptake or swelling, or affinity for hydrophilic drugs. In a similar sense, this can also be achieved when using diisocyanate species in which one or more NCO functional groups are sterically hindered and not readily involved in crosslinking. An example of this is LDI, among others. When the same number of moles of LDI as HDI were incorporated into the crosslinking formulation, the LDI crosslinking network resulted in a lower crosslinking density than the HDI crosslinking network. The reduced crosslinking of LDI may be a result of the difference in reactivity of the two isocyanate groups in LDI. The 2-isocyanate group of ethyl(2S)-2,6-diisocyanatohexanoate is less reactive due to steric effects. This may result in some LDI being simply monofunctionally tethered to the network and not forming bifunctional crosslinks, due to steric hindrance on the 2-isocyanate group of LDI. The unreacted isocyanate group is most likely to be converted to an amine group, which may also enhance the ability of the LDI-containing matrix to hydrogen bond with the API. This may affect the rate of API release.

[0063]

[0099] Suitable monofunctional isocyanates include, but are not limited to, octyl isocyanate, butyl isocyanate, tolyl isocyanate, toluenesulfonyl isocyanate, chlorosulfonyl isocyanate, fluorophenyl isocyanate, 4-chloro-3-(trifluoromethyl)phenyl isocyanate, or (tert-butyl)phenyl isocyanate. Blends of monofunctional and bifunctional isocyanates were examined by combining HDI with octyl isocyanate (OI) in various HDI:OI ​​ratios of approximately 0.55:0, 0.4:0.3, 0.27:0.6, and 0.13:0.9 vol:vol (HDI:OI ​​100:0, 75:25, 50:50, 25:75 molars). A solid, transparent, bubble-free PGSU elastomer was formed at all ratios, but the elastomer gradually became softer with increasing OI and decreasing HDI. The crosslinking density (mol / L) of these PGSU elastomers decreased accordingly, by more than tenfold from HDI:OI ​​100:0 to 25:75 mol:mol. This approach, combining monofunctional and polyfunctional isocyanates, may be a suitable method for achieving mechanically softer and faster-degrading polyester urethane formulations.

[0064]

[0100] By changing the stoichiometric ratio of polyol to polyacid in polyester resins, for example from 1:1 to 1.1:1 mole:mol, more hydrophilic chain ends are produced, increasing intermolecular interactions between soft segment polymer chains and affecting the functional behavior in terms of both polymer degradation and sustained release of supported APIs. API release can be sustained by non-covalent interactions between the hydroxyl groups of the polyol and the APIs. Non-covalent interactions may include, but are not limited to, hydrogen bonds, ionic interactions, hydrophobic interactions, or combinations thereof. The particle size of the APIs can also affect the polymer degradation and API release rates. Furthermore, this 1.1:1 stoichiometric ratio may be used to adjust the molecular weight of the polymer, and in the case of triols such as glycerol, it may support the synthesis of more linear polyester resins due to the more available and thermodynamically favorable primary terminal hydroxyl groups. Excess glycerol produces more primary hydroxyls that react with the polyacid, while the reaction of secondary hydroxyls with the polyacid is statistically less likely, providing greater polyester linearity and more free secondary hydroxyls and / or urethane branching points as pendant groups.

[0065]

[0101] Numerous flexible segment polyester resins were synthesized. Stoichiometric ratios of polyol:polyacid of 1:1 and 1.1:1 were used, but a polyol:polyacid stoichiometric ratio of 0.9:1 is also possible. In some embodiments, the polyol to polyacid stoichiometric ratio is changed, for example, from 1:1 to 0.9:1 molar:mol, resulting in a more polyacid-dominant network. Furthermore, this stoichiometric ratio may support the synthesis of polyester resins with more branching, due to the fact that excess polyacid can target all available hydroxyl groups on triols such as glycerol.

[0066]

[0102] In some embodiments, a catalyst, such as a specific lipase enzyme, is included in the polymerization process to produce a highly linear polyester resin.

[0103] In some embodiments, a chain extender is included in the polyester to increase the distance between the flexible segments and, therefore, increase the mesh size of the crosslinked polymer. This can increase or decrease microphase mixing between the flexible and rigid segments due to thermodynamic incompatibility between segments and greater interphase interactions within the rigid and flexible segments. In some embodiments, the chain extender is incorporated into the rigid segments by first reacting with the diisocyanate and then extending it. This increases the mesh size while ensuring that the distance between the two polyester resin chains remains constant. Alternatively, the chain extender may be added to the PGS side with the catalyst and not to the isocyanate side. This prevents cross-reaction between the chain extender and the isocyanate.

[0067]

[0104] Suitable chain extenders may include, but are not limited to, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, isopentyldiol, 2-methyl-1,3-propanediol, bis(2-hydroxyethyl)terephthalate, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, ethylenediamine, 2-hydroxyethyl-2-hydroxypropanoate, 2,2-bis(hydroxymethyl)propionic acid (DMPA), bis(2-hydroxyethyl)terephthalate (BET), dithiothreitol (DTT), poly(orthoester), or combinations thereof. In some embodiments, diol-based or polyol-based components of various chain lengths and structures may be incorporated into the soft segment during polycondensation reactions with polyols and polyacids, or upstream of polycondensation by first reacting with a polyol and then extending it, or upstream of polycondensation by selectively and partially reacting with a polyacid. Appropriate amounts of chain extenders in a formulation may include, but are not limited to, up to 10% by weight, up to 7% by weight, up to 5% by weight, or up to 2% by weight of the total components of the formulation containing the polyester resin, isocyanate, and any drug, or any value, range, or subrange between these.

[0068]

[0105] In some embodiments, a water-mediated polycondensation process similar to the process disclosed in U.S. Patent No. 9,359,472 is used. In some embodiments, the polyol and polyacid are added simultaneously. In other embodiments, the polyol and polyacid are added stepwise. Furthermore, the reaction can be actively monitored for the concentrations of various additives, such as the polyol and polyacid, to determine the optimal timing for stepwise addition of reagents. A feedback loop may be implemented to provide more precise control over the stoichiometric ratio of the polycondensation additives. Various reaction temperatures, times, and vacuum conditions may be used to obtain the desired results.

[0069]

[0106] In some embodiments, the polycondensation reaction conditions are selected such that the polyester resin has a low M w . The low M w suitable for the soft segment are less than 9000 Da, less than 8000 Da, or less than 6000 Da, or less than 5000 Da, or less than 4000 Da, or less than 3000 Da, or any value, range, or sub-range therebetween, but are not limited thereto. The corresponding number average molecular weight (M n ) can be less than 4000 Da, or less than 3000 Da, or less than 2000 Da, or any value, range, or sub-range therebetween.

[0070]

[0107] In some embodiments, the polycondensation components and reaction conditions are selected such that the soft segment has low branching. As used herein, low branching refers to having less than 15 mol% of 1,2,3-triacylglycerol species when determined by 13 C-NMR. In some embodiments, the soft segment has less than 14 mol%, or less than 13 mol%, or less than 12 mol% of 1,2,3-triacylglycerol species, or any value, range, or sub-range therebetween. As used herein, high branching refers to having more than 15 mol% of 1,2,3-triacylglycerol species when determined by 13 C-NMR.

[0071]

[0108] In some embodiments, polyester resins are synthesized by adding a portion of the monomer components stepwise, dropwise, or in combination thereof to adjust the branching of the polymer chains. Adding polyols to polyacids in small amounts or dropwise can produce more highly branched polyester resin chains, while adding polyacid components to polyols in small amounts can result in less branching in the polyester resin. A stepwise strategy in which the polyester resin is synthesized by repeatedly alternating steps of adding an excess polyacid to a polyol, followed by the addition of stoichiometrically equivalent or excess polyol, and then excess polyacid, can be used to create highly branched polymers.

[0072]

[0109] In some embodiments, the polyester resin is dialyzed before crosslinking to remove residual free polyacids and residual free polyols. In some embodiments, dialyzed is carried out using a 2000 Da cutoff membrane and methanol as the solvent. In some embodiments, dialyzed is carried out using a 2000 Da cutoff membrane and isopropanol (IPA) as the solvent. In some embodiments, too much residual free polyacid can cause bubbles in the formulation due to side reactions between the isocyanate and the acid.

[0073]

[0110] In some embodiments, the polyester resin is dried to remove residual water content before crosslinking. In some embodiments, drying is carried out in a vacuum furnace at about 30°C to about 60°C and about 10 Torre for about 24 hours. In some embodiments, too much residual water content can cause bubbles in the formulation due to side reactions between the isocyanate and water. Appropriate levels of residual water content may include, but are not limited to, less than about 0.1% by weight, less than about 0.05% by weight, or any value, range, or partial range between these.

[0074]

[0111] In some embodiments, the polyester resin is crosslinked with isocyanates in a stoichiometric crosslinking ratio of isocyanate to hydroxyl in the range of approximately 1:1 to 1.1:1. In some embodiments, the polyester resin is melted at approximately 70°C to ensure efficient catalyst incorporation and degassing despite some higher viscosities of the polyester resin. In some embodiments, the polyester resin is cooled to below 35°C before addition and mixing in the crosslinking agent to reduce the possibility of diisocyanate-free acid side reactions. In some embodiments, the speed mixer is also cooled before this step. In some embodiments, crosslinking is allowed to proceed for 24 hours before any further sample handling. In some embodiments, crosslinking is accelerated using temperature increases and / or catalysts to reduce curing time before sample handling.

[0075]

[0112] In some embodiments, the copolymer synthesis process for producing block copolymers, alternating copolymers, or random copolymers is modified to provide the effects of these microstructures on mechanical properties and release dynamics. In some embodiments, the modification affects both the diffusion of water molecules into the polymer structure and the interaction of the chains with the encapsulated API molecules.

[0076]

[0113] In some embodiments, the microstructure of the flexible and rigid segments of the polyester urethane is selected based on the selection of the polyester resin, the diisocyanate crosslinking agent, and the stoichiometric ratio of isocyanate to hydroxyl. In some embodiments, the diisocyanate includes a chain extender. In some embodiments, a free acid is added before crosslinking. In some embodiments, the reaction conditions for crosslinking are also selected to achieve a predetermined microstructure of the flexible and rigid segments.

[0077]

[0114] Regarding mechanical properties, the stiffness of polyester urethane was observed to correlate with the viscosity of the polyester resin, the degree of crosslinking, and the microphase behavior of the resulting polyester urethane. The incorporation of shorter-chain polyacids such as succinic acid and adipic acid resulted in polyester resins where viscosity increased as the polyacid length decreased for a given molecular weight. For example, 8kD poly(glycerol adipate) had a viscosity of 4.53 Pa·s, while 8kD poly(glycerol 50% sebacate-co-50% adipate) had a lower viscosity of 1.85 Pa·s. The longer chain length of sebacate imparts flexibility to the polymer backbone; therefore, shorter polyacids result in polymer chains with lower mobility, lower flexibility, and consequently higher viscosity. Furthermore, since the frequency of ester bonds increases with decreasing polyacid length, the increase in viscosity may be due to an increase in crosslinking via ester bonds between polyester resin chains. Furthermore, adipic acid-containing and succinic acid-containing polyurethane polymers, with the same tendency as viscosity increasing as the carbon chain length of the polyacid decreases, became substantially stiffer when crosslinked to urethane. The longer chain length of sebacic acid imparts flexibility to the polymer backbone that persists in the crosslinked urethane, and therefore, shorter polyacids result in crosslinked urethanes with lower flexibility and thus increased stiffness. The increase in stiffness of polyurethane materials may also be due to increased intermolecular interactions and crosslinking frequency between polyacid groups within the soft segments. Polyacids added in mol% to polyester resin synthesis, such as 5-95 mol%, 10-90 mol%, 20-80 mol%, 25-75 mol%, 50-50 mol%, 75-25 mol%, 80-20 mol%, 90-10 mol%, 95-5 mol%, or any value, range, or partial range between these, combinations of various copolymers of polyacids such as succinic acid, adipic acid, and / or sebacic acid, can be used to adjust the viscosity of the synthetic polyester resin based on the crosslinking density of ester groups and the flexibility of the polyacid chain length. In some embodiments, the polyester urethane comprises a polyester of glycerol and a copolymer of polyacids such as adipic acid and sebacic acid in a molar ratio ranging from 5:95 to 95:5.In some embodiments, the polyester urethane comprises a polyester copolymer of glycerol and succinic acid and sebacic acid in a molar ratio ranging from 5:95 to 80:20.

[0078]

[0115] Suitable polyisocyanates include HDI (log(P) 0.89, where log(P) is the log of the partition coefficient of HDI between octanol and water at infinite dilution), LDI (log(P) 0.76), methylenediphenyl diisocyanate (MDI), toluene diisocyanate (TDI), isophorone diisocyanate (IPDI), tetramethylxylene diisocyanate (TMXDI), dodecamethylene diisocyanate (1,12-diisocyanatododecane or 12DI, theoretical log(P) 6.4 and experimental log(P) 3.559), lysine triisocyanate, (4-isocyanato-phenoxy)acetic acid 2-[2-(4-isocyanato-phenoxy)-hexanoyloxy]-ethyl ester (log(P) 1.28), and 6-(4-isocyanato-phenoxy)-hexanoic acid 2-[6 Examples of polyisocyanates include, but are not limited to, -(4-isocyanato-phenoxy)-hexanoyloxy]-ethyl ester (log(P) 2.77), poly(propylene glycol)trylene 2,4-diisocyanate terminus, 4-isocyanato-ethylene glycol bislactic acid benzoate (log(P) 1.64), poly(hexamethylene diisocyanate), 4,4'-methylenebis(cyclohexyl isocyanate) (H12MDI, log(P) 5.48), 1,3-bis(isocyanate methyl)cyclohexane (BIMC, log(P) 3.92), aliphatic diisocyanates, aromatic diisocyanates, aliphatic-aromatic complex diisocyanates, blocked diisocyanates, polyisocyanates having hydrolyzable groups such as acyl chlorides, anhydrides, or esters in their skeleton, or combinations thereof.

[0079]

[0116] The choice of polyisocyanate can influence numerous properties of the resulting polyester urethane, beyond simply crosslinking the polyester resin. For example, the solubility of the decomposition products can be increased by changing from HDI to a different diisocyanate crosslinking agent. In some embodiments, the crosslinking agent assists decomposition regardless of the molecular weight or polydispersity of the polyester resin, reducing or eliminating the need for molecular weight limitations or compromises. For instance, the resulting elastomer was found to decompose three times faster when crosslinked with LDI than conventional PGSU crosslinked with HDI. Furthermore, the LDI-crosslinked elastomer decomposed while retaining its original shape and was completely solubilized, whereas the conventional PGSU construct crosslinked with HDI lost all its mechanical properties and its original shape before completely decomposing. In some embodiments, LDI-crosslinked polymers exhibit a lower crosslinking density than HDI-crosslinked polymers when mixed in the same isocyanate-to-hydroxyl stoichiometric ratio. LDI-crosslinked elastomers also produced completely water-soluble decomposition products at much higher molecular weights than HDI-crosslinked elastomers, resulting in faster decomposition than HDI in all cases examined. However, the effect of LDI cross-linking on drug release did not follow a universal trend, as will be discussed in more detail below.

[0080]

[0117] For the final crosslinked polyurethanes, the degree of microphase separation, reflected in the difference in log(log(P)) of the partition coefficient between the crosslinking agent and the octanol in the polyester resin and water (Δlog(P)), as well as the degree of crystallinity of the rigid and flexible segments, resulted in polyurethanes with various viscoelastic behaviors. Increasing the degree of microphase separation imparts increased stiffness and strength. Mechanical stiffness is a good example of the effect of differences in polyol microstructure, even for equivalent urethane crosslinks based on the same isocyanate-to-hydroxyl stoichiometric ratio. This demonstrates the effect of using urethane crosslinking to stabilize the polyol microstructure and preserve its physical effects. The crosslinking agent-mediated effect on solubility was observed when using crosslinking agents with log(log(P)) of the partition coefficient between octanol and water ranging from 0 to 0.8. LDI has a log(P) of 0.76. More hydrophobic crosslinking agents, including HDI with log(P) values ​​of 0.8 to 6.5, were also examined. In one example, PGS-HDI required 15 weeks (approximately 105 days) to completely solubilize in an aqueous medium in an accelerated study at 70°C, with the resulting degradation products having an overall Mw of 545 Da and an overall Mn of 387 Da. In contrast, PGS-LDI, prepared using the same polyester resin, required only 35 days to completely solubilize in an aqueous medium under the same conditions, with the resulting degradation products being significantly larger, with an overall Mw of 13,004 Da and an overall Mn of 1,455 Da. This suggests that PGS-HDI required many more hydrolytic chain cleavage events before the polymer network could finally be completely solubilized, whereas PGS-LDI could be completely solubilized after far fewer hydrolytic events. LDI reduces the need for rapid and / or frequent hydrolysis of polymer bonds to decompose the polymer network. LDI helps larger polymer chains enter the aqueous solution, which helps in achieving complete solubilization. In another example, PGS crosslinked with 12DI showed even slower degradation than conventional PGSU crosslinked with HDI.

[0081]

[0118] An example that reflects this behavior is the combination of a more hydrophilic polyacid and a lower M with a more hydrophilic crosslinking agent having a lower log(P) value. w The use of polyester resins having a higher log(P) value is one example, resulting in better phase mixing and significantly softer and more elastic polyurethane. When the crosslinking agent is replaced with a more hydrophobic HDI having a higher log(P) value, the lack of pendant groups on the crosslinking agent, as well as the increase in log(P), resulted in more microphase separation and crystallinity within the rigid segments. w When more hydrophobic polyester resins such as PGS were combined with LDI, the pendant lysine groups on the crosslinking agent disrupted the packing of the rigid segments, despite the increase in Δlog(P). This is a non-trivial phenomenon that can be used to control the degree of microphase separation to improve sustained drug release while preserving the desired mechanical properties. In another example, the same high M w By combining PGS with larger, more hydrophobic linear crosslinking agents such as 12DI, a significantly stiffer, more crystalline polyurethane material is produced, which is also the same high M crosslinked with HDI. w It decomposed more slowly than PGS. A key observation in this invention was the effect of the functional groups and polarity of the rigid segments on microphase separation. The use of isocyanate-based crosslinkers (HDI and 12DI) having low polarity and linear structures reduces intermolecular interactions between the rigid and flexible segments, resulting in crystalline polyurethane materials with a high degree of microphase separation. On the other hand, isocyanate-based crosslinkers such as LDI, which have functional groups that result in hydrogen bonding and other interactions between the rigid and flexible segments, reduce microphase separation. The resulting decrease in stiffness is exemplified by various PG:Seb-based and PG:Ad-based polyester resin formulations combined with LDI. Again, despite the decrease in stiffness of the PGS resin-LDI formulations, the sustained release kinetics were improved, indicating non-trivial interactions that may be attributable to a combination of ester crosslinking within the polyester resin, the crosslinking density of the polyurethane, and the microphase interactions between the rigid segments of the urethane and the flexible segments of the polyester.

[0082]

[0119] Surprisingly, using different diisocyanates in the same molar ratio resulted in different crosslinking densities, as determined by solvent swelling tests. Similarly, when polyester resins were combined with isocyanate-based crosslinking agents, it was observed that the stiffness of the cured polyurethane material did not necessarily correlate with the crosslinking density, as determined by solvent swelling tests. Both stiffness and crosslinking density by solvent swelling are bulk physical measures of the polymer mesh microstructure. On the other hand, the isocyanate-to-hydroxyl stoichiometric ratio describes the components added to the formulation, but does not necessarily describe how the resulting polyester urethane is physically or chemically arranged or structured. All formulations were crosslinked with isocyanate-to-hydroxyl stoichiometric ratios ranging from 1.1:1 to 1:1. Furthermore, a wide variety of crosslinking densities were achieved. A wide variety of mechanical properties were also achieved. For crosslinking agents that react more slowly than HDI, such as LDI, lower crosslinking densities (1.058 mol / L for LDI compared to 1.8–2.2 mol / L for HDI) resulted in softer and more elastic materials. The slower reactivity of LDI may be a result of steric hindrance due to the presence of lysine groups. When larger linear diisocyanate crosslinking agents (12DI) were used, the resulting materials were more vitreous and rigid, despite lower crosslinking densities reported in swelling tests (1.252 mol / L). This is a non-trivial feature, demonstrating that the mechanical properties of crosslinked polyurethanes do not depend solely on the crosslinking density. Another non-trivial feature was that the crosslinking density does not necessarily depend on the stoichiometric ratio of isocyanate to hydroxyl.

[0083]

[0120] While the polymer libraries outlined herein can have varying crosslinking densities based on the stoichiometric ratio of isocyanate to hydroxyl, the polymer libraries also offer the opportunity to modulate polymer degradation without altering the crosslinker-to-hydroxyl ratio. In such cases, this approach focuses on increasing network hydrolysis by altering the composition of the polyacids, resulting in constructs with a more degradable timeframe without adversely affecting mechanical integrity, extractable and leached material levels, shelf life, crosslinking density, or polymer mesh size. In some embodiments, the resulting crosslinking density of the polymer network based on the physical mesh size of the polymer varies among various soft and hard segment formulation combinations, despite a consistent crosslinking ratio of approximately 1:1 to 1.1:1 is maintained during formulation mixing. This highlights that the resulting urethane crosslinking microstructure is a subtle difference and depends on many factors, even when attempting to control the equimolar proportions of isocyanate (NCO) and hydroxyl (OH) components in the mixture. These factors may include, but are not limited to, the properties of the components such as hydrophobicity / hydrophilicity, polarity, molecular weight, branching, packing, radius of inertia, or spatial reachability; the properties of the formulation such as the content of free monomers or residual water; and the properties of the crosslinking reaction such as the efficiency or rate of the urethane reaction.

[0084]

[0121] In some embodiments, the polyester resin and / or diisocyanate are combined with a solvent before combining the polyester resin and diisocyanate. Suitable organic solvents may or may not include acetone, propyl acetate, tetrahydrofuran (THF), ethyl acetate, butyl acetate, dichloromethane (DCM), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methanol, ethanol, IPA, or combinations thereof. In some embodiments, the solvent is a mixture of acetone and propyl acetate in a 50:50, 10:90, 25:75, 75:25, or 90:10 v:v%, or a partial range between these. When the solvent is added to the soft segment polymer, suitable amounts of solids may or may not include 10–90% by weight, 40–60% by weight, or 40–80% by weight, or any value, range, or partial range between these, with the remainder being the solvent. In other embodiments, the polyester resin and diisocyanate are combined in the absence of a solvent, and the polyester urethane formulation comprises the polyester resin, optional additives such as crosslinking agents, chain extenders or free acids, and optional APIs, wherein the flexible segment and the entire formulation are solvent-free.

[0085]

[0122] In some embodiments, the free acid additive is included before crosslinking. In some embodiments, the free acid increases the hydrolysis rate of the polyester urethane through acid-catalyzed hydrolysis. Suitable free acids may or may not include tartaric acid, acetic acid, citric acid, glycolic acid, or lactic acid. In some embodiments, the solid free acid is mixed into the polyester resin immediately after melting to ensure a more homogeneous distribution. In some embodiments, the free acid additive is maintained in a solid state as a dispersion to avoid cross-reactions and to ensure that the free acid can later solubilize and catalyze.

[0086]

[0123] Instead of incorporating shorter polyacids in polyol synthesis, shorter free acids were added to the formulation during the urethane crosslinking step, remaining in the network as catalysts for the hydrolysis process and accelerating decomposition. These free acids can be monoacids, diacids, or polyacids. In particular, DL tartaric acid had a unique effect on the decomposition kinetics of PGSU compared to acetic acid, citric acid, and lactic acid. Free acids can be added from 0.1% to a maximum of 1% by weight without negative consequences to the properties of the formulation, such as side reactions causing carbon dioxide bubbles, and tartaric acid can be added up to a maximum of 5% by weight, still yielding good polyester urethane properties. Adding a small amount of tartaric acid, around 0.1% by weight, to the formulation increased the mass loss of PGSU from 24% to 55% after 4 weeks in an aqueous medium under accelerated conditions (70°C). Furthermore, unlike other free polyacids, free tartaric acid was incorporated into the crosslinked polymer network at up to 5% by weight, and no noticeable bubbles arose from the acid-diisocyanate side reactions observed with other acids at even lower concentrations, around 1% by weight. This may be because the tartaric acid was incorporated as a solid rather than a liquid during mixing into the formulation. It has been shown that when additives or drugs are mixed into the formulation as solid, insoluble particles, they do not readily cross-react with isocyanates during urethane crosslinking. In contrast, acid additives added to PGSU in liquid state may cross-react with isocyanates as a side reaction, potentially causing the formation of carbon dioxide, which may be present as bubbles.

[0087]

[0124] In some cases, the HDI crosslinking network degraded more rapidly due to acid-catalyzed hydrolysis when tartaric acid was incorporated into the formulation as a free acid, but surprisingly, the LDI crosslinking network did not degrade more rapidly in the presence of tartaric acid. This may indicate a specific and selective relationship between HDI and tartaric acid, which function well against acid-catalyzed hydrolysis.

[0088]

[0125] In some embodiments, rigid segments provide mechanical strength, while flexible segments contribute to the flexibility of the polyester urethane material. The approaches described herein can be adapted to increase the degree of microphase mixing by increasing the intermolecular interactions between the rigid and flexible segments, resulting in a softer, more flexible material with lower crystallinity, applicable to soft biodegradable polymer coatings. In other embodiments, in contrast, increasing microphase separation can result in distinct regions of crystallinity between the rigid and flexible segments, increasing the mechanical strength of the material for applications requiring support for long-term cyclic use.

[0089]

[0126] In some embodiments, a polyester urethane is supported with a drug or API for controlled release of the drug or API, and the drug or API is added either during polyester resin formation or during crosslinking with diisocyanate. Suitable APIs may include, but are not limited to, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, bimatoprost, risperidone, naproxen, ibuprofen, nepafenac, amfenac, pyrantel pamoate, trenbolone acetate, or their prodrugs, nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen, ibuprofen, amfenac, or their prodrugs, steroids, hormones, prostamides, antibiotics, antioxidants, antivirals, antiretrovirals, antipsychotics, and other drug types. Suitable APIs may include small molecules, peptides, proteins, antibodies, oligonucleotides, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), cytokines, and growth factors.

[0090]

[0127] In some embodiments, a delayed release mechanism is created by a spatial microstructure arrangement due to hydrophobic shielding, where higher concentrations of rigid segments are present on the outside of the polyester urethane structure. In some embodiments, the drug release delay mechanism is tuned by the concentration or arrangement of rigid segments, primarily through the appropriate chemical selection of soft and rigid segments.

[0091]

[0128] Regarding the degradation behavior, water uptake can be regulated by the chemistry of the hard / soft segments, as well as the spatial arrangement of the phase-separated polyurethane microstructure. Since API release may partially depend on the diffusion of water into the polymer matrix and the limiting diffusivity-based and / or affinity-based interactions that retain the API within the polymer, these factors also significantly influence the sustained release tendency.

[0092]

[0129] In some embodiments, the mesh size of the polyester-urethane crosslinked network affects the permeability and diffusion of water molecules, drug molecules, and polymer degradation products through the polymer matrix. For example, small molecules and peptides up to approximately 4–6 kDa can permeate a PGSU matrix based on high molecular weight PGS with a stoichiometric ratio of 1:1 glycerol:sebacic acid crosslinked with HDI at an isocyanate to hydroxyl stoichiometric ratio of 1.1:1–1:1. However, larger molecules such as proteins having 22 kDa, 66 kDa, and 150 kDa cannot easily permeate the PGSU matrix, possibly due to the mesh size filtration effect. Increasing the mesh size can increase water infiltration into the polymer network and accelerate degradation. Increasing the mesh size can also accelerate release kinetics.

[0093]

[0130] In exemplary embodiments, microphase separation of soft and hard segments due to chemical differences such as hydrophilicity / hydrophobicity increases the duration of drug release. Differences in polarity between hard and soft segments result in hydrophilic vs. hydrophobic properties. For example, a mismatch between hydrophilicity and hydrophobicity between the soft and hard segments resulted in an increased duration of dexamethasone release. In one example, three types of polyesters were synthesized and fabricated into urethanes using either LDI or HDI (see Example 32). Polyester urethanes derived from low molecular weight PGS synthesized using a stoichiometric ratio of glycerol:sebacic acid in combination with HDI resulted in an increased duration of release compared to the same low molecular weight PGS combined with LDI. Similarly, PG:Ad synthesized in a stoichiometric ratio of glycerol:adipic acid at 1.1:1 molar:mol and combined with HDI resulted in an increased duration of release compared to the same PG:Ad combined with LDI. Unexpectedly, and in contrast, high molecular weight PGS-derived polyester urethanes synthesized with a glycerol:sebacic acid stoichiometric ratio of 1:1 and combined with LDI demonstrated the opposite trend compared to the same high molecular weight when combined with HDI, resulting in an increased release duration. These polyester urethanes were formulated with either LDI or HDI at equivalent isocyanate-to-hydroxyl ratios in the range of 1:1 to 1.1:1. In all cases, LDI helped enable faster degradation of the polyester urethane network compared to HDI, but in all other cases, LDI also resulted in a faster release duration of the hydrophobic drug dexamethasone, and therefore a decrease in the release duration.

[0094]

[0131] High molecular weight PGS-LDI presented an interesting situation where the release of the hydrophobic drug dexamethasone was slowed compared to high molecular weight PGS-HDI, deviating from the trends of other observed formulations. This is useful because most other formulations that degrade faster also suffer from faster release, while allowing formulations that degrade faster but offer increased duration of release. The improved sustained release with high molecular weight PGS-LDI may be due to the increased degree of phase separation between the highly branched hydrophobic PGS chains and the hydrophilic lysine-terminated LDI. The rate of crosslinking by LDI was slower than with HDI. This may provide more time for phase separation to occur between the soft and hard segments of the polymer matrix, potentially creating larger pockets of hydrophobic PGS regions crosslinked with isocyanates.

[0095]

[0132] In some embodiments, polyester urethane is supported with 60% by weight of an NSAID and molded into shapes such as discs or rods for oral, intraocular, or subcutaneous delivery. In some embodiments, the molded shape is coated with an unsupported polymer such as conventional PGSU to moderate and control drug release.

[0096]

[0133] For example, low molecular weight PGS with low branching crosslinked with HDI degraded faster than conventional PGSU derived from high molecular weight and high branching PGS crosslinked with HDI, but released dexamethasone more slowly. While we do not wish to be bound by theory, it is thought that shorter PGS chains have a higher frequency of ester bonds, allowing for faster degradation and being more linear, but they have more penetrating hydroxyl groups available for isocyanate attack in urethane crosslinking, forming a network with soft segments mainly along the polymer backbone and hard segments mainly as orthogonal branches. By retaining ester bonds mainly within the polymer backbone in less branched and more linear resins, when formed in a polyester-urethane network, it may allow for more water interactions with those ester bonds. Similarly, by retaining urethane bonds that mainly form branches in less branched and more linear resins, when formed in a polyester-urethane network, it may allow for more drug interactions with those urethane bonds.

[0097]

[0134] In some embodiments, the synthesis / crosslinking reaction rate of resins synthesized using more than one polyacid is adjusted to create distinct PG:Ad / PG:Suc / PG:Seb regions. These alternating or random crystalline soft segment regions containing different polyacids can impart physical and chemical properties that can be used to adjust mechanical properties and / or API release. For example, a PG:[25:75]Ad:Seb polyester resin formulated to include a polyester urethane construct supported with 60 wt% dexamethasone (see the beginning of the Examples section for resin nomenclature) imparted sufficient hydrophobic crystalline regions of sebacic acid-rich soft segments from which release can persist.

[0098]

[0135] Variations in the polyacid ratio during copolymer synthesis can be used to adjust the release dynamics of hydrophobic APIs. Similar to the phenomenon observed in decomposition rates, the use of PG:[50:50]Ad:Seb polyester resin in polyester urethane did not result in release curves for any API that fell exactly midway between the release curves of PG:Seb and PG:Ad alone.

[0099]

[0136] For example, polymers of glycerol, polyacid, and diisocyanate were supported at 60% by weight with an API, which is a nonsteroidal anti-inflammatory drug (NSAID). The hydrophobic NSAID drug had a solubility of approximately 50 μg / mL in PBS and was encapsulated within a polymer matrix of PGAdU. A more rapid drug release profile was observed compared to conventional PGSU, with more than 40% of the drug payload released within the first two weeks. However, when the same hydrophobic drug was encapsulated within a polymer matrix of PG:[50:50]Ad:Seb-U, a slower release profile was obtained, with only 10-20% of the drug released within the first two weeks, which is very close to the release profile observed when the drug is released from a polymer matrix of conventional PGSU, where approximately 10% of the API payload was released within the first two weeks. However, in another embodiment, when the same polymer material was supported with the hydrophobic drug dexamethasone, which has a solubility of approximately 75 μg / mL in PBS, the release of the API from PG:[50:50]Ad:Seb-U was much closer to the release profile of its release from PG:Ad-U than from PGSU.

[0100]

[0137] The microstructural arrangement of the soft segments of PG:Suc, PG:Ad, and / or PG:Seb affects not only the frequency of ester bonds and thus the rate of hydrolysis, but also the crystalline behavior of each segment. When soft segments are combined as block copolymers, the entire polyester urethane may exhibit physical, chemical, mechanical, decomposition, and release properties as two separate materials. When the copolymer combination is synthesized as alternating chains of PG:Suc, PG:Ad, and / or PG:Seb, adjacent polyacid segments may exhibit unexpected effects on decomposition and release kinetics. For example, contrary to what has been reported in the literature on polyethylene oxide (PEO) and polycaprolactone (PCL) copolymers, where the incorporation of PEO blocks into PCL-PEO-PCL ternary block copolymers or a reduction in the length of PCL segments has been shown to increase hydrolysis and decrease crystallinity, the microstructure of the polyester resin can instead be arranged in a way that does not affect crystallinity, or even increases crystallinity while simultaneously accelerating hydrolysis. For example, a particular crosslinking agent may better mix with a specific region of a polyester resin, leading to an acceleration of the crosslinking reaction rate.

[0101]

[0138] Various polyols and polyacids can be selected for their polarity, increased hydrophilicity, and therefore increased interaction with water for hydrolysis. In addition to the chemical composition of the constituent elements, the structure can also be selected for increased access to water for hydrolysis. Structural features may include, but are not limited to, the degree of branching, the spacing between branching points, the length of the branches, the spacing between ester bonds, and / or the spacing between urethane bonds.

[0102]

[0139] Distribution can be caused by a number of factors, including but not limited to: drug miscibility in the soft segment, drug miscibility in the hard segment, drug solubility in aqueous media, the distribution coefficient (log(P)) of the drug between octanol and water, drug mobility, drug permeability in the polymer phase, drug diffusivity in the polymer phase, drug affinity to the soft segment, drug affinity to the hard segment, non-covalent interactions with the soft segment, non-covalent interactions with the hard segment, drug dispersion in the soft segment, drug dispersion in the hard segment, drug-drug interactions, temperature during compounding, drug melting temperature, crystallization temperature, and glass transition temperature, and / or drug solubility in any solvent system used during compounding.

[0103]

[0140] Therefore, considering the distribution possibilities, the order of addition of components during the mixing step is important. The drug may first be added directly to the polymer, first to the isocyanate, or first to a pre-mixed polymer-isocyanate blend. In a solvation system, the drug may first be added to the solvation system. In a solvation system, the drug may be dissolved in the solvent and then mixed with the polyester resin, isocyanate, or pre-mixed polymer-isocyanate blend. Appropriate conditions may help stabilize the drug in an amorphous state in the PGSU matrix. The presence of a solvent may affect the distribution of the drug and the spatial arrangement of the polymer.

[0104]

[0141] In some embodiments, the drug is first added to the polymer, and then the isocyanate is added in a second mixing step. In some embodiments, it may be preferable to allow equilibration between mixing steps, giving time for any arrangement or rearrangement. When multiple types of polymers are blended together, the order of addition is again important. In some embodiments, it may be preferable to first mix the hydrophobic drug with the hydrophobic sebaciate-containing polymer, and then add the hydrophilic polymer to the mixture. This allows for favorable interaction between the hydrophobic polymer and the hydrophobic drug before adding other formulation components, providing good affinity between the two, good drug dispersion, and good drug encapsulation. Stepwise addition of drugs, resins, or isocyanates may be necessary. In some embodiments, stepwise addition of drugs in multiple mixing steps optimally incorporates and disperses the drugs.

[0105]

[0142] Regarding these mixing considerations, wetting of drug particles by the formulation components is important for good dispersion and a good interface between the drug particles, which have no air gaps and / or porosity, and the crosslinked polymer network. Both drug-polymer dispersion and the drug-polymer interface affect the release kinetics. Drug release kinetics, in turn, affect the polymer degradation rate due to the porosity left by the drug particles. Drug particle size and shape, drug dispersion, or drug aggregation significantly affect drug release kinetics and polymer degradation kinetics (see, for example, Examples 28 and 29). Surface tension and surface energy of all components, as well as attractive and repulsive forces between components, should also be considered. Various polyester urethane compositions achieve different dispersion and wetting behaviors of APIs.

[0106]

[0143] Various polyester urethane compositions achieve different rheological behaviors. Resin viscosity and rheology are another important factor driving the distribution and wetting of drug particles, as well as the homogeneous mixing of all components. For example, adipic acid-containing resins and succinic acid-containing resins exhibited higher viscosity than sebaciic acid-containing resins, with succinic acid compositions exhibiting the highest viscosity of all, nearly non-flowing at compounding temperatures in the range of 25°C to 45°C. This makes adipic acid a preferred polyacid over succinic acid, among other influences on decomposition. While molecular weight is a common tunable factor related to viscosity, how the viscosity of branched polymers tends to behave with their molecular weight is not always predictable. For example, low molecular weight PGS exhibited lower viscosity than high molecular weight PGS, making them easier to mix, compound, flow, and dispense, or extrude or mold. In another example, low molecular weight PGS synthesized with a glycerol:sebacic acid stoichiometric ratio of 1:1 is similar to low molecular weight PGS synthesized with a glycerol:sebacic acid stoichiometric ratio of 1.1:1. w Having a molecular weight of approximately 6,000 Da, the former had a high degree of branching with approximately 15 mol% of 1,2,3-triacylglycerides, while the latter had a low degree of branching with approximately 11 mol%. The former had a viscosity of approximately 1.5 Pa·s, while the latter had a viscosity of approximately 1 Pa·s. This comparison emphasizes that molecular weight cannot unilaterally predict viscosity, and that the degree of branching also plays a similar role.

[0107]

[0144] In some embodiments, all formulation components are added stepwise and mixed using high-shear-speed mixing. In some embodiments, speed mixing generates heat. If the temperature of the formulation mixture exceeds the glass transition temperature of the drug, the mobility of the drug in the amorphous state may increase. This can result in increased distribution in the soft or hard segments, depending on the affinity of the drug to the polymer components.

[0108]

[0145] Temperature is important during compounding because it affects the viscosity and polymer chain mobility of these polyester resins. The resin temperature has various effects on the orientation of linear polymer chains compared to branched polymer chains. Temperature also affects the mobility of rigid and flexible segments of the polymer. This can lead to preferential distribution of drugs in either segment. In some embodiments, a given temperature is selected to induce aggregation and condensation of the flexible segments, while another temperature may allow the flexible segments to mix more readily with other compounding components. Various polyester urethane compositions achieve different miscibility behaviors of the resin and diisocyanate. This may be due to viscosity differences between the resin and the isocyanate, or it may be due to differences in solubility, polarity, or surface energy. For example, diisocyanate is not readily incorporated into adipic acid-containing resins or succinic acid-containing resins, even under high shear mixing, and is not miscible, compared to sebaciic acid-containing resins.

[0109]

[0146] In some embodiments, solvating the resin affects viscosity and, therefore, drug dispersion. For example, viscosity was significantly reduced by preparing soft segments in solution using acetone and / or propyl acetate with a polymer content of 40–60 wt%. The solvated formulations were easier to process, mix, flow, and extrude. In a specific example, P[1:1]G:[50:50]Ad:Seb(8k)-HDI (14-HDI, see Table 1 for resin abbreviations), prepared with G:Ad-S 1:1 mol:mol and Ad-S 50–50 mol%, was solvated for formulation. The resulting solvated drug-loaded grafts demonstrated sustained release of one specific hydrophobic drug (a nonsteroidal anti-inflammatory drug (NSAID) with log(P) 1.9 and a solubility of 50 μg / mL in phosphate-buffered saline (PBS)), showing a longer duration of release compared to a different hydrophobic drug (a corticosteroid with log(P) 1.93 and a solubility of 75 μg / mL in PBS) loaded onto the solvent-free version of the same formulation. In both formulations, neither drug showed solubility in any formulation component, including the polyester resin, isocyanate, and solvent, if present. Unexpectedly, in this case, the solvated formulation released the drug more slowly than the solvent-free version, which was the opposite of the trend observed previously. While we do not wish to be bound by theory, it is thought that the solvated formulation has a larger mesh size in the crosslinking network due to polymer swelling and spacing during crosslinking, followed by solvent evaporation. This typically allows for greater drug and water permeability and diffusion through the polymer network compared to solvent-free formulations, resulting in faster release kinetics. There is also some evidence that solvated formulations degrade faster than solvent-free formulations. Furthermore, there is evidence that solvated formulations of PGSU release drugs faster than solvent-free PGSU for a wide range of drugs. The favorable extended release kinetics observed with solvated 14-HDI having G:Ad-S 1:1 mol:mol and Ad-S 50-50 mol% may be due to better drug wetting and dispersion resulting from lower viscosity.Another possibility is that the presence of a solvent induces specific interactions between the soft and hard segments, resulting in greater drug distribution to a given phase or greater phase separation. The presence of a solvent may orient the soft and / or hard segments of the crosslinked polymer to reduce water infiltration. Alternatively, the increase in mesh size left due to solvent evaporation may increase the flexibility, and therefore the surface area available for the drug to interact once released. Another possibility is that two different hydrophobic drugs may exhibit different release kinetics in the same soft and hard segment composition due to any differences in partition coefficient, solubility, polarity, particle size, particle morphology, and interactions with the hard and soft segments.

[0110]

[0147] As support for the concept that different hydrophobic drugs can exhibit different release kinetics from the same soft segment, it was observed that the release into PBS of two different hydrophobic APIs (APIs) differed when embedded in polymer matrices with different ratios of adipic acid and sebacic acid content. The two hydrophobic APIs were dexamethasone, with a log(P) of 1.93 and a solubility of approximately 75 μg / mL in PBS, and an NSAID, with a log(P) of 1.9 and a solubility of 50 μg / mL in PBS. Both drugs were released more slowly in polymer matrices where the polyester resin was composed of 1-HDI, and much more rapidly from matrices where the polyester resin was composed of 7-HDI. However, in a matrix where the polyester resin was composed of 14-HDI with an adipic acid to sebacic acid ratio of 1:1, dexamethasone was released relatively rapidly, with approximately 63% of the payload released in two weeks, compared to approximately 67% in two weeks for the 7-HDI formulation, in contrast to 1-HDI where only about 22% was released in two weeks. Conversely, hydrophobic NSAIDs were released much more slowly from 14-HDI, with 10-20% of the drug payload released in the first two weeks, compared to the 7-HDI formulation where more than 40% of the drug payload was released in the first two weeks, and were released almost as slowly as the 1-HDI formulation, where approximately 10% of the drug was released in the first two weeks. These findings demonstrate that predicting the release kinetics of a given API from various soft segments is not as simple as simply comparing the hydrophobic monomer content in the polyester resin with the hydrophilic monomer content.

[0111]

[0148] In some embodiments, the spatial arrangement of soft and hard segments alters water penetration and thus contributes to the rate of hydrolysis. Phase separation can be utilized to create a "shielding" of the soft segments based on intermolecular interactions between the divided soft and hard domains. Hard segment domains may be preferentially oriented toward the surface, possibly as a result of molding, intermolecular interactions between segments, or thermodynamic phenomena. When exposed to an aqueous medium, the hard segments can act as a shield on the water-exposed surface, while the soft segments remain internal and less accessible to water. This, therefore, can result in slower degradation or shielding of hydrolysis when the hard segments are more crystalline and the soft segments are more amorphous.

[0112]

[0149] In some embodiments, increased phase separation leads to increased mobility of the soft segment, resulting in a transition of the soft segment to a more favorable thermodynamic state by minimizing interfacial free energy. The soft segment itself may also undergo phase separation or autoaggregation, where the hydrophilic glycerol-rich hydroxyl-containing domains of the polymer network are spatially harmonized, as are the hydrophobic sebaciate-rich carboxyl-containing and aliphatic chain-containing domains of the polymer network. In this case, a preferential orientation of hydroxyl groups toward the outward side of the soft segment domain occurs due to interaction with water, while carboxylic acid groups aggregate inward relative to the domain and interact with the encapsulated drug particles. This particular spatial arrangement of the soft segment domain may offer the advantage of exposing the hydrolyzable chain segment to water while simultaneously protecting and retaining the API, and thus sustaining its release. One reason why more hydrolyzable polyester resins, such as poly(glycerol adipate) (PG:Ad), are not readily achievable after further crosslinking using urethane chemistry is that the crosslinked final product may lose its faster hydrolytic properties and degradation advantages due to the stability of the urethane bonds. This prospect is more likely when using higher concentrations of diisocyanate crosslinking agents, for example, for isocyanate-to-hydroxyl stoichiometric ratios in the range of approximately 1:1 to 1.1:1. However, the polyester urethane library described herein shows that the higher rate of hydrolysis observed in the prepolymer usually proceeds to the post-crosslinked polyester urethane state despite the presence of "non-degradable" urethane bonds. The degradation profile of these particular polyester urethanes is governed by water uptake. The higher the ability to absorb water into the matrix, the greater the potential for faster hydrolysis. Furthermore, the mobility of the degradation products aids in permeability through and desorption of the bulk network.Shorter-chain polyacids such as adipic acid and succinic acid, as well as their corresponding oligomers with polyols and isocyanates, can pass through polymer mesh networks more easily than sebacic acid and its similar oligomers. Shorter-chain polyacids such as adipic acid and succinic acid may also be able to catalyze ester hydrolysis with acid more than sebacic acid due to increased maneuverability in approaching and cleaving multiple ester bonds.

[0113]

[0150] In some embodiments, filling soft segment polymer chains with low molecular weight soft segments improves sustained drug release. In some embodiments, the low molecular weight is less than approximately 6,500 Da by weight average and less than approximately 2,500 Da by number average. For example, low molecular weight soft segments unexpectedly resulted in improved sustained release of dexamethasone.

[0114]

[0151] In some embodiments, filling of soft segment polymer chains based on low branching of soft segments improved sustained drug release. As previously stated, low branching refers to a degree of branching (DOB) of less than approximately 15% molar of 1,2,3-triacylglycerides or less than 0.36 DOB = 2D / (2D+L) (where D represents the molar percentage of 1,2,3-triacylglycerides and L represents the combined molar percentage of 1,2-diacylglycerides and 1,3-diacylglycerides). For example, a low degree of branching of soft segments unexpectedly resulted in improved sustained release of dexamethasone. Soft segments with lower molecular weights had lower molar percentages of 1,2,3-triacylglycerides.

[0115]

[0152] In some embodiments, filling the flexible segment polymer chains with long polyacid components of the flexible segment improves sustained drug release. Higher molecular weight polymers of the long polyacid component of the present invention have carbon chain lengths of 8 or more and exhibited better sustained release compared to shorter polyacids. While we do not wish to be bound by theory, this may be due to the effect of higher branching of the polymer chains and a higher density of disintegrative spatial arrangement of the chains. This enhances the hydrophobic interactions between the polymer and the API and the physical encapsulation of the API. Furthermore, this hydrophobicity of the polymer matrix also affects the infiltration of water molecules into the matrix, which helps to provide better sustained release of the API. For example, the use of sebacic acid with 8 carbon atoms and a linear structure improved the sustained release of dexamethasone compared to adipic acid or succinic acid, which have 4 and 2 carbon atoms and also have a linear structure, respectively. Furthermore, as the number of carbon atoms in the polyacid component increases, the polarity and hydrophilicity of the polymer chains decrease. As a result, the interaction between the rigid and soft segments is reduced, while the interdomain interactions within the soft segments increase, leading to more interaction with the encapsulated hydrophobic API particles.

[0116]

[0153] In some embodiments, the packing of rigid segment polymer chains based on long linear diisocyanate components of the rigid segments improved sustained drug release. The long diisocyanate components of the present invention have a carbon chain length of 6 or longer. For example, the use of HDI having 6 carbon atoms and a linear structure improved the sustained release of dexamethasone over LDI having 5 carbon atoms and a branched pendant portion. In one surprising contrasting example, when the soft segment was purely a PGS of any molecular weight or branching, the use of LDI improved the sustained release of dexamethasone over HDI, highlighting that perhaps hydrophilic / hydrophobic differences may be a key mechanism that promotes the formation of more packed crystalline soft segment regions.

[0117]

[0154] In some embodiments, the packing of rigid segment polymer chains based on the long linear diisocyanate component of the rigid segment also influences degradation. For example, the use of 12DI, which has 12 carbon atoms and a linear structure, slowed degradation even further than HDI, which has 6 carbon atoms and a linear structure. LDI, which has 5 carbon atoms and a pendant moiety, showed the fastest degradation of all three. Again, the increased degree of interdomain interaction and more phase separation within the rigid segment led to increased crystallinity, which slowed the diffusion of water into the polymer matrix.

[0118]

[0155] In some embodiments, the hydrophobicity of the soft segment based on sebacic acid improved the sustained release of hydrophobic drugs. For example, the use of hydrophobic sebacic acid improved the sustained release of dexamethasone compared to hydrophilic adipic acid or hydrophilic succinic acid. A glycerol:sebacic acid molar ratio of 0.9:1 can be a useful soft segment composition due to its higher sebacic acid content, and therefore higher hydrophobicity and lower polarity.

[0119]

[0156] In some embodiments, the hydrophobicity of the soft segments based on glycerol, adipic acid, and / or succinic acid accelerates the degradation rate. For example, the use of hydrophilic adipic acid or succinic acid accelerated the degradation rate more than hydrophobic sebacic acid. Sebacic acid is thought to be more hydrophobic than adipic acid or succinic acid due to its longer aliphatic chain. Unexpectedly, poly(glycerol adipate) (PGAd) was observed to degrade significantly faster than PGS, even at very high crosslinking densities. This effect has been observed with thermosetting resins using short-chain acids with low tetrahydrofuran (THF) permeability (see Godinho et al.), but this effect observed with crosslinked versions that mimic the thermosetting properties of the resin is unexpected. While we do not wish to be bound by theory, the rate of decomposition is thought to be governed by the number of ester bonds in the polyester exceeding the urethane crosslinks in the matrix, progressing from longer diacides (sebacic acid) to shorter diacides (adipic acid, succinic acid). Ester bonds increase the rate of decomposition because they make the system more hydrophilic. Chain filling of the resin with the help of crosslinking creates a denser network, thus causing a reduction in THF permeability. However, in the presence of water, this effect is reduced, in some cases due to the rate of hydrolysis and increased water permeability resulting from increased hydrophilicity of the matrix.

[0120]

[0157] In some embodiments, the hydrophilicity of the hard segments based on LDI accelerates the decomposition rate. For example, the use of hydrophilic LDI accelerated the decomposition rate more than hydrophobic HDI. HDI is thought to be more hydrophobic than LDI due to its slightly longer aliphatic chains, and LDI is also more hydrophilic due to the esters present in its pendant groups.

[0121]

[0158] In one example, replacing 50 mol% of sebaic acid in a polyester resin with adipic acid and crosslinking the resulting resin with HDI produced degradation products more than twice as large as those of conventional PGSU. In contrast, replacing adipic acid with succinic acid, a shorter polyacid, resulted in only a slight increase of approximately 30% in the solubility of the degradation products, which was within the statistical error of adipic acid. This indicates a specific range of polyacid lengths that yields desirable tunable benefits. Specifically, and unexpectedly, partially replacing an 8-carbon polyacid with a 4-carbon polyacid resulted in a significant increase in the solubility of the degradation products, which was statistically no different from the effect observed when replacing an 8-carbon polyacid with a 2-carbon polyacid. A polyester urethane polymer prepared using a prepolymer substituted with 50 mol% adipic acid decomposed five times faster and became completely solubilized than conventional PGSU prepared using the same crosslinking density. Succinic acid was observed to be incorporated at a slower rate than adipic acid and sebacic acid during the water-mediated polycondensation reaction with glycerol, and not to the same extent as them. Therefore, the chain structure of glycerol adipate-sebacate (GAd:Seb) is likely to be quite different from that of glycerol succinate-sebacate (GSuc:Seb), although this is difficult to determine or quantify. In relation to this, the biodegradate structure, its repeating unit pattern, and its solubility differ between GAd:Seb and GSuc:Seb. The solubility of sebacic acid in water is 0.25 mg / mL compared to the solubility of adipic acid (24 mg / mL) and succinic acid (58 mg / mL). Incorporating shorter diacitors yields polyester urethane formulations that produce more soluble degradation monomers and oligomers, increasing the average water solubility of the polyacid components. For example, [25:75]Ad:Seb has an average solubility of 6.19 mg / mL, [50:50]Ad:Seb has an average solubility of 12.13 mg / mL, and [50:50]Suc:Seb has an average solubility of 29.13 mg / mL.

[0122]

[0159] In some examples, polymers containing copolymers of two different polyacids exhibited degradation kinetics closely matching those of polymers with shorter polyacids, but showed softer mechanical properties and better drug release profiles than polymers with longer polyacids. In some examples, 95:5, 80:20, 75:25, 50:50, 25:75, 20:80, or 5:95 mol% succinic acid-sebacic acid (Suc:Seb) or adipic acid-sebacic acid (Ad:Seb) copolymers behaved more similarly to one acid or the other acid, rather than similarly to the two mean or expected weighted mean, due to the polymer structure being more gradient copolymer and less random polymer (see, for reference, "Gradient copolymers - Preparation, properties and practice," European Polymer Journal, Vol. 116, pp. 394-414, (2019)). This approach has resulted in biodegradable polyester urethanes that adapt some of the storage stability, low extractable and leached content, high crosslink density, and low mesh size of conventional PGSUs, achieving surprisingly 2 to 7 times faster degradation rates. In some embodiments, PG:Ad using 100% adipic acid provides faster degradation. In some embodiments, PG:[50:50]Ad:Seb and PG:[50:50]Suc:Seb using adipic acid:sebacic acid 50:50 mol:mol and succinic acid:sebacic acid 50:50 mol:mol, respectively, provide faster degradation and sustained release of some drugs. In some embodiments, PG:[25:75]Ad-Seb using adipic acid:sebacic acid 25:75 mol:mol still provides faster degradation while also providing sustained release. In some embodiments, PG:[95:5]Suc:Seb has a very high viscosity that is on the boundary of workability, but these formulations may decompose the fastest of all, providing contributions of shorter diacids and more ester bond frequencies for enhanced hydrolysis.

[0123]

[0160] In fact, some biodegradable polyester urethanes made with flexible segments composed of polyacids shorter than sebaciacin, partially or entirely, appeared to crosslink 2–4 times more than conventional PGSU when reacted with the same amount of diisocyanate in the same isocyanate-to-hydroxyl stoichiometric ratio, based on Florey-Löner solvent swelling tests. Surprisingly, however, they decomposed 2–7 times faster than conventional PGSU, highlighting the unexpected effect of hydrolysis of the flexible segments on polymers composed of 20% non-degradable rigid segments.

[0124]

[0161] Furthermore, prepolymers prepared using two different polyacids—one short and one long—into polyester urethanes might be expected to exhibit hydrolysis and degradation profiles that are a linear combination of the expected degradation characteristics of each individual polyacid alone. However, in some cases, these polyester urethanes were found to exhibit hydrolysis and degradation profiles that were very similar to those of the shorter polyacid alone and less similar to those of the longer polyacid. Consequently, they had faster degradation times than the expected average. However, the presence of the longer polyacid resulted in a more viable, more suitable, and softer mechanical property of the final polyester urethane polymer, and a lower viscosity resin with hydrophobic regions in the network, compared to polymers prepared using only the shorter polyacid, which enhances the sustained drug release of hydrophobic drugs.

[0125]

[0162] Furthermore, prepolymers containing one short polyacid and one long polyacid yielded copolymers with a lower degree of branching than equivalent molecular weight polymers containing the shorter polyacid alone. In some cases, it was observed that soft segments with a lower degree of branching but similar molecular weight, when crosslinked with diisocyanates, produced polymers with a more favorable sustained dexamethasone release profile. The molar percentage of 1,2,3-triacylglycerides, an indicator of branching determined by 13C-NMR, was 14.1 mol% for PG:Ad(8k) with a weight-average molecular weight of approximately 8,000 Da, while PG:[50:50]Ad-Seb(8k), a copolymer of equimolar sebaciate and adipic acid of similar molecular weight, had a lower molar percentage of 1,2,3-triacylglycerides at 13.1 mol% (see Example 4).

[0126]

[0163] In some embodiments, two or more polyester resins having different polyacid compositions are blended together as polyester resins for crosslinking with diisocyanates, increasing the hydrolysis rate of the resulting polyester urethane compared to conventional PGSU. In some embodiments, physical blending achieves the arrangement of various polyacid regions in the resulting polyester urethane.

[0127]

[0164] In some cases, significantly viscous but equally hydrolyzable prepolymers with inherent processability problems were blended with less viscous prepolymers to create a more processable, homogeneous prepolymer blend, which was then successfully crosslinked using diisocyanates to form a degradable polyester urethane with a more hydrolyzable network component. In some examples, the resulting polymer had two distinct soft segment components that could provide a wider range of physicochemical and mechanical properties. The polyester resins needed to have a certain degree of miscibility with each other. When PG:[95:5]Suc:Seb and PG:Seb were left at room temperature for 10 minutes, they separated into two distinct layers, which were then rapidly mixed and crosslinked to form a polyester urethane. The resulting polymer exhibited two-phase decomposition, which resulted in polymer cracking and an unpredictable degradation profile. On the other hand, PG:[95:5]Ad:Seb, when mixed with PG:S to form a transparent and homogeneous composition, exhibited a faster degradation kinetic than conventional PGSU, resembling a more hydrolyzable network and mimicking the degradation profile of a homogeneous network. Furthermore, the copolymer of adipic acid and sebacic acid, replacing the direct poly(glycerol adipate) in the mixture, achieved better mixing and homogeneity in the blend.

[0128]

[0165] In some embodiments, free acid additives contained in the polyester urethane composition act as blowing agents through the generation of carbon dioxide gas. The synchronized generation of carbon dioxide gas and crosslinking of the polyester urethane act to encapsulate gas particles and produce a foamed material. The concentration and size of the pores can be adjusted by controlling the crosslinking and carbon dioxide generation. Alternatively, physical pologens can be included in the polyester urethane formulation and leached out after crosslinking to create a porous substrate. Foamed materials can be beneficial in applications requiring rapid diffusion and payload release, facilitating the release and delivery of large molecular substances that would otherwise remain encapsulated within non-foamed crosslinked substrates. Foamed substrates also facilitate the infiltration of cells and biological materials in applications related to bioabsorbable grafts. Furthermore, porous polyurethane materials are commonly used in orthopedic applications requiring resistance to compressive stress, made possible by the synchronized viscoelastic behavior and water-filled pores of the polyester urethane.

[0129]

[0166] In addition to adjusting the length of the polyacid, or alternatively, the polyol can be modified to similarly alter the frequency and spacing of the ester bonds. Suitable alternative polyols may or may not be limited to polyethylene glycol or polyorthoesters. Polyorthoesters may be incorporated to introduce hydrolysis sites with significantly faster degradation rates. In some embodiments, the polyol component includes a mixture of two or more polyols, such as glycerol and PEG300. Various combinations of polyols may be used, such as 5-95 mol%, 10-90 mol%, or 20-80 mol%, or 25-75 mol%, or 50-50 mol%, or any value, range, or partial range in between.

[0130]

[0167] In some cases, the interactions between some of the parameters used to regulate the solubility of the degradation products were also non-trivial and unexpected. For example, a lower molecular weight PG:Seb polyester resin with an Mw of approximately 6,000 Da, combined with an LDI crosslinking agent, produced a polyester urethane degradation product with twice the number-average molecular weight (Mn) of the degradation product of a higher molecular weight PG:Seb polyester resin with the same crosslinked Mw of approximately 15,000 Da and the same crosslinked LDI density (see Example 21). The Peak 1 degradation product of the LDI polyester urethane formed from low Mw PG:Seb showed Mn 13,186 Da, compared to Mn 5,917 Da for the Peak 1 degradation product of the LDI polyester urethane formed from higher Mw PG:Seb, as measured by gas permeation chromatography (GPC). However, the Mw of these maximum degradation products was more similar for the low MW PG:Seb-LDI polyester urethane at 19,858 Da compared to 17,540 Da for the higher Mw PG:Seb-LDI polyester urethane. Considering the entire population of degradation products, the low Mw PG:Seb-LDI polyester urethane produced lower Mw degradation products (10,893 Da) than the higher Mw PG:Seb-LDI polyester urethane (13,004 Da). The ratio of large to small degradation products differed between these two formulations. Also in this example, for both the higher Mw PG:Seb and the lower Mw PG:Seb, LDI crosslinking resulted in these large-sized degradation products that were completely water-soluble. This is in contrast to the same higher Mw PG:Seb crosslinked with HDI, whose degradation products needed to be very small in size to be completely water-soluble. Specifically, the peak 1 degradation product showed Mn 1,482 Da and Mw 1,670 Da, while the overall degradation product population was Mw 545 Da.

[0131]

[0168] The acidity of monomers, oligomers, and decomposition products, as well as the solubility of the decomposition products, can help accelerate decomposition by acid-catalyzed hydrolysis of ester bonds. Succinic acid, as a diprotic acid, has two pKa values ​​of 4.21 and 5.64 at 25°C. Adipic acid has two pKa values ​​of 4.41 and 5.41. The strongest pKa value of sebacic acid is 4.72. Lower pKa values ​​reflect stronger acids and a higher ability to donate protons in aqueous solution. This makes succinic and adipic acids more acidic and thus better suited to acid-catalyzed hydrolysis.

[0132]

[0169] The ability of degradation products to leave the polymer network also influences whether the polymer is surface-erosive or bulk-degradable. Even in the absence of solubility, maneuverability, or discharge of biodegradables, the polymer network still undergoes some hydrolytic cleavage, but its dimensions and mass do not decrease over time. If the degradation of the polymer network and its degradation products are not solubility-limited, dimensional and mass losses can occur in a controlled manner at predictable rates. Furthermore, residual degradation products can delay degradation by preventing sufficient water interaction for hydrolysis, which may apply to residual sebacic acid given its nonpolarity, hydrophobicity, and water insolubility.

[0133]

[0170] In addition to providing more soluble degradation products, LDI has the further advantage of being a much more biocompatible diisocyanate crosslinker than HDI, considering that LDI decomposes into lysine and ethanol, whereas HDI is converted to hexamethylenediamine (HDA), which is a concern for toxicity in vivo, during degradation. Generally, hydrolysis of the amide bonds of urethane components produces carbamic acid, which is inherently unstable and reacts rapidly with water to form amines and carbon dioxide, respectively, which are evacuated and exhausted. When HDI is the crosslinker in PGSU, the HDA produced by hydrolysis may exhibit acute toxicity via oral and inhalation routes and moderate toxicity via the skin route, although HDA does not induce skin sensitization, is not a developmental or reproductive toxin, and may only cause limited systemic damage, with any irritation observed being proportional to the HDA exposure concentration. In particular, HDA is rapidly absorbed and metabolized in vivo and shows little tissue storage. HDA is partially oxidized to 6-aminohexanoic acid by diaminooxidase and aldehyde dehydrogenase, which is excreted in the urine, while a small portion of HDA is also excreted in the urine unchanged. Importantly, the excretion of HDA by humans is rapid, within 10 hours. In contrast to HDA, lysine and ethanol do not pose the same toxicity concerns.

[0134]

[0171] Another non-obvious advantage of using LDI over other diisocyanates is the biocompatibility of its degradation products, which are lysine and ethanol. Lysine is a naturally occurring essential amino acid that is a precursor to many proteins, and it can suitably interact with naturally occurring metabolites that make up polymer backbone, such as sebacic acid, adipic acid, succinic acid, and / or glycerol. Sebacic acid is known to reduce postprandial hyperglycemia in individuals with type 2 diabetes. Lysine is also known to be helpful in blood glucose management. Combinations of biodegradable products derived from LDI-containing and sebacic acid-containing polyester urethanes are likely to be useful in metabolic management and diabetes.

[0135]

[0172] Another non-trivial advantage of using LDI is that its degradation product, ethanol, may help solubilize oligomers during PGSU network degradation. Ethanol is a good semipolar solvent for glycerol, sebacic acid, adipic acid, succinic acid, oligomers containing these components, and polymers containing these components. In particular, for non-water-soluble PGS and PGSU biodegradates and / or oligomers that typically lose water solubility at sizes greater than 1000 Da, the small amount of ethanol produced by LDI hydrolysis may help bring these degradation products into solution. While we do not wish to be bound by theory, this may be one mechanism by which LDI overcomes the water solubility limit of PGS and PGSU biodegradates and oligomers.

[0136]

[0173] Another mechanism by which LDI improves the water solubility of PGS and PGSU species may be that LDI, based on its hydrophilicity, allows more solvent to penetrate into the polymer matrix. Polymer dissolution occurs in two stages. First, solvent molecules diffuse through the polymer matrix, forming a swollen mass known as a gel. Second, the gel collapses, and the molecules are dispersed into a true solution. In one instance, LDI allows PGS and PGSU biodegradables to form a true solution in an aqueous medium, which occurs much faster in time and with much larger molecular weight species in a true solution compared to HDI. LDI provides a more favorable hydrophilic environment for water molecules to diffuse into the outer layers of the PGSU network, aiding hydrolysis. LDI also allows for more swelling, which further generates more water molecules, likewise aiding hydrolysis.

[0137]

[0174] In some embodiments, both water uptake and swelling are important attributes influenced by the hydrophilicity of the network. Drug release and hydrolytic degradation of polymers depend on access to water molecules. The water contact angle of a polymer network can be used to understand its hydrophilicity and potential for water interaction. To improve water interaction, it may be desirable to have a contact angle less than 60 degrees, less than 45 degrees, less than 30 degrees, or any value, range, or partial range between these. For example, the use of hydrophilic adipic acid, succinic acid, and / or LDI improved water uptake and increased water swelling. When a surface erosion mechanism of hydrolytic degradation is desired, water uptake and swelling may need to be minimized. For example, the use of 100% sebaciate as a polyacid in polyester crosslinked with HDI or 12DI reduced water uptake and decreased water swelling. For surface erosion, it may be desirable to have a contact angle greater than 60 degrees, greater than 70 degrees, greater than 80 degrees, or any value, range, or partial range between these to reduce water interaction. When a bulk degradation mechanism is suitable, water uptake and swelling can be maximized as means to accelerate degradation. If the polyester urethane microstructure contains highly phase-separated soft segment regions and hard segment domains, water infiltration and corresponding drug release and hydrolytic degradation may follow different kinetic velocities and different physical and spatial pathways through the polymer microstructure compared to soft and hard segment microstructures that are not well phase-separated.

[0138]

[0175] In any formulation, it is important to maintain the acid value below 75 or 70 mgKOH / g to avoid bubbles from side reactions between isocyanates and carboxylic acids that release carbon dioxide during formulation. The acid value of the resin can be controlled during synthesis by having fewer penetrating carboxylic acids and / or fewer free polyacid monomers and polyacid-containing oligomers. Unreacted monomers and oligomers can also be purified and removed by dialysis after synthesis.

[0139]

[0176] The functional behavior of these crosslinked polyester urethane polymers was evaluated by examining a range of quality attributes important for pharmaceuticals and medical devices, including real-time degradation kinetics, accelerated degradation kinetics, drug release kinetics, drug-polymer interactions, drug-polymer spatial structure, crosslinking, water uptake, water swelling, solvent swelling, sol content, extractables and leached materials, and mechanical properties.

[0140]

[0177] In some embodiments, the polyester urethane compound comprises a polyester resin, a crosslinking agent, and one or more optional additives such as a chain extender, a free acid, an API, or a combination thereof, wherein the flexible segment of the polyester resin is first solubilized in a solution, where acetone and / or propyl acetate may be preferred organic solvents.

[0141]

[0178] In some embodiments, the unsupported polyurethane formulation proceeds stepwise, where the crosslinking agent and catalyst are added to two separate portions of the polyester resin to facilitate double-barrel extrusion, at which point crosslinking is initiated by the mixing of the polyester resin, crosslinking agent, and catalyst. For both the catalyst (side A) and the crosslinking agent (side B), the resin is first added to a speed mixer cup and mixed at 2500 RPM for 2 minutes while drawing vacuum into the cup. Next, the catalyst and crosslinking agent, along with any additives such as acid additives or chain extenders, are added to their respective cups, and a pin mixer is placed in each cup and mixed again at 250 RPM for 2 minutes under vacuum. Subsequently, each side A and B is loaded into a double-barrel syringe, which is further mixed at 2000 RPM under vacuum for final degassing. A static mixing tip is attached to the end of the double-barrel syringe, and a hydraulic piston is used to push the material from both syringe chambers through the mixing tip to the final mold.

[0142]

[0179] Numerous isocyanates were tested, and all polyester resins were crosslinked with a crosslinking ratio of isocyanate to hydroxyl in the range of approximately 1:1 to 1.1:1. Crosslinking was allowed to proceed for 24 hours, after which any further sample manipulation was performed.

[0143]

[0180] Several unsupported compositions were molded into macroscale shapes with a thickness of several millimeters. The unsupported compositions were tracked for mass loss throughout their degradation under real-time (37°C) or accelerated (70°C) degradation conditions, under orbital stirring at 180–240 rpm in 0.1 M PBS pH 7.4.

[0144]

[0181] In some embodiments, the supported polyurethane formulation proceeds stepwise, where the crosslinking agent and catalyst are added to two separate portions of the polyester resin mixed with the API to facilitate double-barrel extrusion, at which point the reaction chemistry begins within the mixing chip. First, the polyester resin is weighed separately into cup A and cup B and speed-mixed at 2500 RPM for 2 minutes while drawing vacuum into the cups. Next, the API is added to each side according to the ratio of resin in each cup and speed-mixed at 2500 RPM without vacuum or pin mixer to ensure complete incorporation of the API into the resin. Then, a pin mixer is added and the resin / API blend in both sides A and B is mixed again at 2500 RPM for 2 minutes under vacuum. After confirmation of API incorporation, the catalyst and crosslinking agent are added to each side A and B and mixed at 2500 RPM for 2 minutes under vacuum. Both sides are supported in a double-barrel syringe, which is further mixed at 2000 RPM under vacuum for final degassing. A static mixing tip was mounted at the end of a double-barrel syringe, and a hydraulic piston was used to push the material from both syringe chambers through the mixing tip to the final mold.

[0145]

[0182] Several compositions were loaded with 60% by weight of dexamethasone and molded into microscale grafts having a diameter of 450 micrometers and a length of 10 millimeters. The dexamethasone-loaded compositions were tracked for mass loss and dexamethasone release throughout the entire degradation under real-time conditions (37°C) with orbital stirring at 50–150 rpm in 0.1 M PBS (pH 7.4).

[0146]

[0183] In some embodiments, PGX-based polyurethane formulations with a crosslinking range of isocyanate to hydroxyl stoichiometric ratios of 1:1 to 1.1:1 were formed using drug loading rates of 0 to 80% by weight, where selected crosslinkers, polyester resins, and additive chemistry facilitated polyurethane microstructures that allowed for drug release and polymer degradation by surface erosion.

[0147]

[0184] In some embodiments, the microstructure, phase mixing, differential dispersion properties, and / or differential flow properties arrange zones within the three-dimensional spatial volume of the components, such as a drug gradient, drug-rich or drug-poor zones, crosslinker rigid segments, or polymer flexible segments, for example, axial or radial zones for the inflow and movement of water and / or drugs.

[0148]

[0185] In some embodiments, the polyester urethane is poly(glycerol adipate)urethane (PG:Ad-U) (PG:Ad-HDI) using glycerol for the polyol component, adipic acid for the polyacid component, and HDI for the isocyanate component. This results in a more hydrophilic soft segment and a more hydrophobic hard segment.

[0149]

[0186] In some embodiments, the polyester urethane is PG:Ad-LDI, which uses glycerol for the polyol component, adipic acid for the polyacid component, and LDI for the isocyanate component.

[0150]

[0187] In some embodiments, the polyester urethane is PG:Seb-HDI, using glycerol for the polyol component, sebacic acid for the polyacid component, and HDI for the isocyanate. This yields hydrophobic soft and hard segments.

[0151]

[0188] In some embodiments, the polyester urethane is P[1.1:1]G:Seb-HDI, which uses glycerol for the polyol component, sebacic acid for the polyacid component, and HDI for the isocyanate component, with a stoichiometric ratio of polyol:polyacid of 1.1:1.

[0152]

[0189] In some embodiments, the polyester urethane is PG:Seb-LDI, using glycerol for the polyol component, sebacic acid for the polyacid component, and LDI for the isocyanate component. This results in a more hydrophobic soft segment and a more hydrophilic hard segment.

[0153]

[0190] In some embodiments, the polyester urethane is P[1.1:1]G:Seb-LDI, which uses glycerol for the polyol component, sebacic acid for the polyacid component, and LDI for the isocyanate component, with a stoichiometric ratio of polyol:polyacid of 1.1:1.

[0154]

[0191] In some embodiments, the polyester urethane is poly(glycerol sebacate-co-adipate)urethane (PG:Ad:Seb-HDI) using glycerol for the polyol component, a combination of sebatic acid and adipic acid for the polyacid component, and HDI for the isocyanate component.

[0155]

[0192] In some embodiments, the polyester urethane is poly(glycerol sebacate-co-adipate)urethane (PG:Ad:Seb-LDI) using glycerol for the polyol component, a combination of sebatic acid and adipic acid for the polyacid component, and LDI for the isocyanate component.

[0156]

[0193] In some embodiments, the polyester urethane is poly(glycerol sebacate-co-succinate)urethane (PG:Suc:Seb-HDI) using glycerol for the polyol component, a combination of sebaic acid and succinic acid for the polyacid component, and HDI for the isocyanate component.

[0157]

[0194] In some embodiments, the polyester urethane is poly(glycerol sebacate-co-succinate)urethane (PG:Suc:Seb-LDI) using glycerol for the polyol component, a combination of sebacic acid and succinic acid for the polyacid component, and LDI for the isocyanate component. These result in a slightly hydrophobic soft segment and a more hydrophilic hard segment. LDI helps to accelerate degradation, and adipic acid or succinic acid also helps to accelerate degradation. Sebacic acid helps to sustain drug release.

[0158]

[0195] In some embodiments, the polyester urethane is P[1.1:1]G:Ad-HDI, which uses glycerol for the polyol component, adipic acid for the polyacid component, and HDI for the isocyanate component, with a stoichiometric ratio of polyol:polyacid of 1.1:1.

[0159]

[0196] In some embodiments, the polyester urethane is P[1.1:1]G:Ad-LDI, which uses glycerol for the polyol component, adipic acid for the polyacid component, and LDI for the isocyanate component, with a stoichiometric ratio of polyol:polyacid of 1.1:1.

[0160]

[0197] In some embodiments, the polyester urethane is PG:[50:50]Suc:Seb-HDI, which uses glycerol for the polyol component, a combination of 50 mol% sebaciate and 50 mol% succinic acid for the polyacid component, and HDI for the isocyanate component.

[0161]

[0198] In some embodiments, the polyester urethane is low in glycerol and sebaciate. w This is a PG:Seb-LDI using LDI for the polyester resin and isocyanate components.

[0162]

[0199] In some embodiments, the polyester urethane is low in glycerol and sebaciate. w The LDI is a polyester resin and an isocyanate component, and PG:Seb-LDI+0.1TA is used with 0.1% by weight of tartaric acid.

[0163]

[0200] In some embodiments, the polyester urethane is P[1.1:1]G:[50:50]Ad:Seb[D]-HDI, which is a dialyzed polyester resin with a polyol:polyacid stoichiometric ratio of 1.1:1 and a combination of 50 mol% sebaciate and 50 mol% adipic acid as the polyacid component, and an HDI for the isocyanate component.

[0164]

[0201] In some embodiments, the polyester urethane is a dialyzed polyester resin [D] with a polyol:polyacid stoichiometric ratio of 1.1:1, a combination of 50 mol% sebaciate and 50 mol% adipic acid for the glycerol and polyacid components, an HDI for the isocyanate component, and G:[50:50]Ad:Seb[D]-HDI using 0.1 wt% tartaric acid.

[0165]

[0202] In some embodiments, the polyester urethane is a polyester resin blend consisting of 50% by weight of a first polyester resin, which is a combination of glycerol and adipic acid in a polyol:polyacid stoichiometric ratio of 1:1, 95 mol%, and sebacic acid in a second polyester blend, which is a combination of glycerol and sebacic acid in a polyol:polyacid stoichiometric ratio of 1.1:1, and is defined as [50:50P[1:1]G:[95:5]Ad:Seb+P[1.1:1]G:Seb]-LDI, which is an LDI for the isocyanate component.

[0166]

[0203] In some embodiments, the polyester urethane is P[1:1]G:[25:75]Ad:Seb-HDI, which is a polyester resin with a polyol:polyacid stoichiometric ratio of 1:1, and a combination of 75 mol% sebaciate and 25 mol% adipic acid for the polyacid component, as well as an HDI for the isocyanate component.

[0167]

[0204] In some embodiments, the polyester urethane is P[1:1]G:[25:75]Ad:Seb-HDI+0.1TA, which uses a polyester resin with a polyol:polyacid stoichiometric ratio of 1.1:1, a combination of 75 mol% sebaciate and 25 mol% adipic acid for the polyacid component, HDI for the isocyanate component, and 0.1 wt% tartaric acid.

[0168]

[0205] In some embodiments, the polyester urethane is P[1:1]G:[25:75]Ad:Seb-LDI, which is a polyester resin with a polyol:polyacid stoichiometric ratio of 1:1 and a combination of 75 mol% sebaciate and 25 mol% adipic acid for the polyacid component, and LDI for the isocyanate component.

[0169]

[0206] In some embodiments, the polyester urethane is P[1.1:1]G:Seb-HDI+0.1TA, using 0.1% by weight of glycerol for the polyol component, sebacic acid for the polyacid component, HDI for the isocyanate component, and tartaric acid for the isocyanate component.

[0170]

[0207] In some embodiments, the polyester urethane is low in glycerol and sebaciate. w This is a PG:Seb-HDI using HDI for polyester resin and isocyanate components.

[0171]

[0208] In some embodiments, the polyester urethane is P[1:1]G[50:50]Ad:Seb-HDI, which uses glycerol for the polyol component with a polyol:polyacid stoichiometric ratio of 1:1, a combination of 50 mol% sebaciate and 50 mol% adipic acid for the polyacid component, and HDI for the isocyanate component.

[0172]

[0209] In some embodiments, the polyester urethane is formed from a polyester resin that has an acid value of less than 75 and a hydroxyl value of less than 240, and is crosslinked with diisocyanate.

[0173]

[0210] In some embodiments, the polyester urethane is formed from a polyester resin having an acid value of less than 60 and a hydroxyl value of less than 220, and is crosslinked with diisocyanate.

[0174]

[0211] In some embodiments, the polyester urethane is formed from a polyester resin crosslinked with diisocyanate, having an acid value higher than 35 and a hydroxyl value higher than 2180.

[0175]

[0212] In some embodiments, the polyester urethane is formed from a polyester resin having a zero shear viscosity of less than 5 Pa·s, compounded at or below 60°C, and crosslinked with diisocyanate. In some embodiments, the polyester urethane is formed from a polyester resin having a zero shear viscosity of less than 3.5 Pa·s, compounded at or below 30°C, and crosslinked with diisocyanate. In some embodiments, the polyester urethane is formed from a polyester resin having a zero shear viscosity of less than 2 Pa·s, compounded at or below 30°C, crosslinked with diisocyanate, and having a solvent-free drug load of up to 80% by weight.

[0176]

[0213] In some embodiments, the polyester resin comprises glycerol as a polyol and sebacic acid, adipic acid, or succinic acid as a polyacid.

[0214] In some embodiments, the polyester resin comprises glycerol as a polyol and a combination of sebacic acid and adipic acid or succinic acid as polyacids in a polyacid molar ratio ranging from 95:5 to 5:95.

[0177]

[0215] In some embodiments, the polyester resin comprises glycerol as a polyol and a combination of sebacic acid and adipic acid as polyacids, where both polyols are uniformly incorporated during synthesis.

[0178]

[0216] In some embodiments, the polyester resin contains a polyol:polyacid in a stoichiometric ratio of 1.1:1.

[0217] In some embodiments, the polyester resin contains a polyol:polyacid molar:mol ratio of 0.9:1.

[0179]

[0218] In some embodiments, the polyester resin includes a PGS polyester resin crosslinked with LDI. In some embodiments, the PGS polyester resin is low M w This is PGS.

[0180]

[0219] In some embodiments, the polyester resin includes a PGS polyester resin crosslinked with LDI. In some embodiments, the PGS polyester resin is low M w This is PGS.

[0181]

[0220] In some embodiments, low M w The PGS polyester resin has a minimum M of 6,500 Da. w , M less than 2,000 Da n , and has polydispersity of less than 5. In some embodiments, low M w The PGS polyester resin has a minimum pressure of 3,000 Da. w It has a low M. In some embodiments, w The PGS polyester resin has a polydispersity of less than 2.

[0182]

[0221] In some embodiments, the polyester resin comprises glycerol as a polyol and adipic acid as a polyol, has a low to medium molecular weight, and has a fluid viscosity at room temperature, approximately 20-25°C, or below 40°C.

[0183]

[0222] In some embodiments, the polyester urethane is formed from a polyester resin crosslinked by HDI, using glycerol as the polyol and adipic acid as the polyacid. In some embodiments, the stoichiometric ratio of polyol to polyacid is 1.1:1.

[0184]

[0223] In some embodiments, the polyester urethane is formed from a polyester resin crosslinked by LDI, using glycerol as the polyol and adipic acid as the polyacid.

[0185]

[0224] In some embodiments, the polyester resin comprises glycerol as a polyol and a combination of 50:50 mol% sebacic acid and adipic acid as polyacids.

[0225] In some embodiments, the polyester resin comprises glycerol as a polyol and a combination of 25:75 mol% sebacic acid and adipic acid as polyacids.

[0186]

[0226] In some embodiments, the polyester resin comprises glycerol as a polyol and a combination of 75:25 mol% sebacic acid and adipic acid as polyacids.

[0227] In some embodiments, the polyester resin comprises glycerol as the polyol and a combination of 50:50 mol% sebacic acid and succinic acid as the polyacid.

[0187]

[0228] In some embodiments, the polyester urethane includes up to 10 w / w% of a chain extender, which is added during the blending step of the compounding process.

[0229] In some embodiments, the polyester urethane includes a chain extender incorporated with the isocyanate before the blending step during compounding.

[0188]

[0230] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin having an intentional viscosity mismatch.

[0231] In some embodiments, the polyester urethane is formed from isocyanates and polyester resins having intentional mismatches in mismatch.

[0189]

[0232] In some embodiments, the polyester urethane is formed from isocyanates and polyester resins having an intentional hydrophilic-hydrophobic or polarity mismatch.

[0233] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin in the presence of an API having intentional API particle aggregation.

[0190]

[0234] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin in a solvent in the presence of an API insoluble in the solvent to drive the distribution of the API.

[0191]

[0235] In some embodiments, the order of addition of the resin, solvent, API, and isocyanate is selected to obtain a predetermined microstructure of the soft and hard segments.

[0236] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin, where the isocyanate has a partition coefficient log(P) of less than 0.8.

[0192]

[0237] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin, where the isocyanate has a partition coefficient log(P) equal to or greater than 0.8.

[0193]

[0238] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin in the presence of an API, where the API has a partition coefficient log(P) greater than 1.

[0194]

[0239] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin in the presence of an API, where the API has a partition coefficient log(P) equal to or less than 1.

[0195]

[0240] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin in the presence of an API, where the API has a water solubility of less than 100 μg / mL.

[0196]

[0241] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin in the presence of an API, where the API has a water solubility equal to or greater than 100 μg / mL.

[0197]

[0242] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin in the presence of an API, where the diacid component of the polyester has an average water solubility greater than 0.25 mg / mL.

[0198]

[0243] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin in the presence of an API, where the diacid component of the polyester has an average water solubility of 0.25 mg / mL or less.

[0199]

[0244] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin in the presence of an API, where the API has a D50 particle size of less than 10 μm.

[0200]

[0245] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin in the presence of an API, where the API is hydrophobic.

[0246] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin in the presence of an API, where the API is a corticosteroid, steroid, or hormone.

[0201]

[0247] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin in the presence of an API, where the API is an NSAID.

[0248] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin, where the isocyanate is hydrophilic.

[0202]

[0249] In some embodiments, the polyester urethane is formed from isocyanates and polyester resins of polyols and polyacids, where the polyacid is hydrophilic.

[0250] In some embodiments, the polyester urethane is formed from isocyanates and polyester resins of polyols and polyacids, where the polyacid is hydrophobic.

[0203]

[0251] In some embodiments, polyester urethane having a water swelling of less than 10 w / w% is formed from isocyanate and polyester resin.

[0252] In some embodiments, polyester urethane having a sol content of less than 3 w / w% is formed from isocyanate and polyester resin.

[0204]

[0253] In some embodiments, the polyester urethane is formed from isocyanates and polyester resins of polyols and polyacids, where the polyacid includes a long hydrocarbon backbone.

[0205]

[0254] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin, where the isocyanate includes a long hydrocarbon skeleton.

[0255] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin, where the polyester resin has a radius of inertia in the range of 9 to 35 nm.

[0206]

[0256] In some embodiments, the polyester resins of polyols and polyacids contain less than 15 mol% of 1,2,3-triacylglycerides.

[0257] In some embodiments, the polyester resins of polyols and polyacids have a more linear polyester backbone with unreacted secondary hydrochlores for subsequent crosslinking with isocyanates.

[0207]

[0258] In some embodiments, the polyester urethane has isocyanate-crosslinked amide bonds along the polymer backbone at a higher frequency than those imparted to PGSU by sebaciic acid.

[0208]

[0259] In some embodiments, the polyester urethane is formed from a polyester resin having a hydroxyl value greater than 180 due to isocyanate and hydroxyl-API interactions.

[0209]

[0260] In some embodiments, the polyester urethane is formed from a polyester resin having an acid value greater than 30 due to isocyanate and carboxylic acid-API interactions.

[0210]

[0261] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin, where the isocyanate includes a monofunctional isocyanate coupled with a difunctional isocyanate.

[0211]

[0262] In some embodiments, the polyester urethane is formed from an isocyanate and a polyester resin, where the isocyanate comprises a monofunctional isocyanate coupled with a difunctional isocyanate, where the monofunctional isocyanate contains pendant functionality for API interaction.

[0212]

[0263] While the applications described herein have primarily focused on drug delivery for sustained drug release, the polyester urethanes disclosed herein may also have microstructures selected by the same principles as described for other purposes.

[0213]

[0264] In some embodiments, the polyester urethane bioabsorbable elastomers described herein are used in biomedical engineering applications requiring bioabsorbable grafts or graft components. In some embodiments, the polyester urethane bioabsorbable elastomers described herein are used as polymer networks for the controlled release of drugs and / or biopharmaceuticals, or as structural medical devices or medical device components.

[0214]

[0265] In some embodiments, the microstructure of the polyester urethane described herein is selected for compounding with non-pharmaceutical fillers or additives, where similar principles described herein may be applied to compound such polyester urethane compositions.

[0215]

[0266] In some embodiments, a polyester resin composed of one or more polyacids can be used as an in-situ gel without urethane crosslinking. In some embodiments, the polyester resin is modified to incorporate reversible crosslinking.

[0216]

[0267] In some embodiments, the polyester urethane bioabsorbable elastomers described herein are used in biomedical applications as bioabsorbable grafts or graft components. In some embodiments, the polyester urethane bioabsorbable elastomers described herein are used as bioabsorbable coatings, films, fibers, textiles, microspheres, nanospheres, microneedles, or scaffolds. In some embodiments, the polyester urethane bioabsorbable elastomers described herein are used as polymer networks for controlled release of drugs and / or biopharmaceuticals, or as structural medical devices or medical device components.

[0217]

[0268] In some embodiments, the adjustable microstructure of the polyester urethane described herein is selected for use in non-pharmaceutical applications where drugs may not be present, such as medical devices and cell therapies. In some embodiments, the polyester urethane bioabsorbable elastomers described herein are selected using various polyacids and / or to adjust the synthesis of copolymers, thereby catalyzing a side reaction that produces carbon dioxide, and thereby producing polyester urethane foams useful in applications such as cell scaffolds.

[0218]

[0269] In some embodiments, the microstructure of the polyester urethane described herein is selected to improve fiber properties for fiber wet spinning, melt spinning, extrusion, electrospinning, and other processes.

[0219]

[0270] In some embodiments, the controlled microstructures of the polyester urethanes described herein are selected for use in film techniques, coating techniques, fiber techniques, additive manufacturing, chemical conjugation / functionalization schemes, and / or cell culture.

[0220]

[0271] In some embodiments, the microstructures of the polyester urethanes described herein are selected for use in particulate and nanoparticle formulations.

[0272] In some embodiments, the microstructure of the polyester urethane described herein is selected for use in a gel drug depot that can be injected in situ.

[0221]

[0273] In some embodiments, the microstructures of the polyester urethanes described herein are selected for use in oral or injectable sustained-release or immediate-release formulations.

[0222]

[0274] In some embodiments, the microstructures of the polyester urethanes described herein are selected for use in targeted release, for example, to target cancer cells using PGX-U that is degraded and released by an acid catalyst for targeted release, or to target adipocytes such as adipose tissue using hydrophobic PGX-U.

[0223]

[0275] In some embodiments, the microstructure of the polyester urethane described herein is selected for use in forming a larger physical mesh size due to the incorporation of a crosslinking agent that can provide a lower crosslink density at an equivalent NCO:OH ratio for the sustained release of larger molecules such as peptides, oligonucleotides, proteins, or monoclonal antibodies, which in other circumstances would remain largely encapsulated within a tightly crosslinked polymer matrix.

[0224]

[0276] In some embodiments, the microstructure of the polyester urethane described herein is selected for use in forming a smaller physical mesh size due to the incorporation of a crosslinking agent that can provide a higher crosslinking density at an equivalent NCO:OH ratio for the sustained release of small molecules that may be difficult to deliver in a sustained manner. For example, small molecules that are highly hydrophilic and highly water-soluble may benefit from the described higher-density crosslinked polyester urethane network. Furthermore, water penetration and permeation can be restricted using the described higher-density crosslinked polyester urethane network, increasing the possibility of surface erosion as a decomposition mechanism.

[0225]

[0277] Any aspect of the embodiments described herein can be readily combined to form alternative further embodiments. [Examples]

[0226]

[0278] The present invention is further described in the context of the following embodiments, which are presented for illustrative purposes only and are not limiting.

[0279] In the following examples, the following abbreviations are used to refer to polyesters and polyester urethane compositions. For polyesters of formulas such as P[1.1:1]G:[25:75]Suc:Seb[D], G represents glycerol, Suc represents succinic acid, Seb represents sebacic acid, [1.1:1] represents the stoichiometric ratio of glycerol to polyacid (in this case, 1.1:1), [25:75]Suc:Seb represents the two polyacids in the polyester (in this case, 25 mol% succinic acid and 75 mol% sebacic acid), and [D] indicates that the polyester was dialyzed after formation. For polyesters of formulas such as P[0.75:0.25:1]G:PEG300:Seb, PEG300 represents polyethylene glycol having an average molecular weight of approximately 300 g / mol as a copolyol with glycerol in this case, with a molar ratio of glycerol:PEG300:sebacic acid of 0.75:0.25:1. For polyesters with formulas such as [50:50P[1:1]G:Ad(2k)+P[1:1]G:Ad(8k)]-HDI+0.1TA, Ad represents adipic acid, [50:50P[1:1]G:Ad(2k)+P[1:1]G:Ad(8k)] represents a 50:50 molar blend of two indicated polyesters crosslinked by polyisocyanate, G:Ad represents a single polyol and a single polyacid in the polyester, and (2k) and (8k) represent the approximate molars of the first and second polyester resins before crosslinking. w (In this case, 2,000 Da and 8,000 Da) is shown, -HDI indicates a polyisocyanate crosslinking agent (HDI in this case), and +0.1TA indicates the presence of added free acid (in this case, 0.1 wt% tartaric acid based on the weight of the polyester urethane). For polyester urethanes of formulas such as P[1:1]G:Ad(8k)-[2:1]HDI:LDI, -[2:1]HDI:LDI indicates that the polyester is crosslinked with a mixture of polyisocyanates with more than one (in this case, a molar ratio of HDI to LDI of 2:1). The stoichiometric ratio of isocyanate to hydroxyl in the examples was approximately 1:1.

[0227] Example 1

[0280] Twenty-seven different polyester resins of copolymers of glycerol and one or more polyacids were synthesized in a 30 L reactor by an aqueous medium polycondensation method. The weight average molecular weight (M w ) and polydispersity index (PDI) were determined by GPC RI for each resin. The results are shown in Table 1.

[0228]

Table 1

[0229]

[0281] The M w values reported in Table 1 are for the undried PGS resin. Resin 1 is a polyester resin for conventional PGSU. Polyester resins 2, 12, 17, and 23 were dialyzed after the polycondensation reaction ([D] indicated). The measured M w values were in the range of 1170 - 25279 g / mol and the PDI values were in the range of 2.3 - 8.5.

[0230] Example 2

[0282] The conversion rates of glycerol (G), sebacic acid (Seb), and adipic acid (Ad) were monitored during the polycondensation to form P[1:1]G:[50:50]Ad:Seb. Figure 1 shows that adipic acid reacted with glycerol significantly faster than sebacic acid.

[0231] Example 3

[0283] The structural parameters and the relative molar fractions of each glyceridic unit in a particular polyester resin were determined during the polycondensation. The polyester resin was sampled over time throughout the synthesis to capture the progress and microstructure of the polycondensation. Collected for each set of samples 11H-NMR data revealed the time-dependent content of each possible monomer in the glycerol-based polymer when sebacic acid, succinic acid, and / or adipic acid were used as the diacid. Figure 2 shows the time-dependent changes in free glycerol (G), free sebacic acid (Seb), free adipic acid (Ad), reacted sebacic acid (pSeb), reacted adipic acid (pAd), 1-acylglyceride (1T), 2-acylglyceride (2T), 1,3-diacylglyceride (13L), 1,2-diacylglyceride (12L), and 1,2,3-diacylglyceride (123D) during the polycondensation that forms PGSAd.

[0232]

[0284] As a structural parameter, the carboxylic acid conversion rate (p COOH ), glycerol substitution degree (DS), glycerol hydroxyl conversion rate (p OH ), and number-average degree of polymerization (DP n ) are examples. The average mole fraction (X) of each glyceride species containing unreacted glycerol (1-acylglyceride (1T), 2-acylglyceride (2T), 1,3-diacylglyceride (1,3L), 1,2-diacylglyceride (1,2L), and 1,2,3-diacylglyceride (1,2,3D)) i ), as well as the relative mole fraction (Y) of each glyceride unit in the polymerization chain. i The results for each polyester were also determined. The final measurement results are shown in Table 2.

[0233] [Table 2]

[0234]

[0285] p COOH , p OH , and DP n The levels of 1,3L, 1,2L, and 1,2,3D increased with reaction time.

[0235] Example 4

[0286] Table 3 shows,13 The relative molar ratios of the microstructure of a particular polyester resin derived from Example 1, as determined by 13C NMR spectroscopy, are shown. Appropriate instrument settings were used to provide sufficient peak resolution to enable quantitative determination of all peaks associated with the acylglyceride moiety. The degree of branching reported in Table 3 was calculated by integrating the peaks in the glyceride region representing 1T, 2T, 1,2L, 1,3L, and 1,2,3D, determining the area under each peak, and determining the percentage of each peak compared to the total glyceride peak in the polymer. Samples were prepared with deuterated acetone at a concentration of 500 mg / mL. The degree of branching was calculated using the formula: degree of branching = 2D / (2D+L) (where D is the amount of 1,2,3D and L is the combined amount of 1,2L and 1,3L).

[0236] [Table 3]

[0237]

[0287] Figure 3 shows a plot of the degree of branching of polyester resins versus the molar ratio of 1,2,3-triacylglycerides. Figure 1 shows that the separation of resins with different degrees of branching is mainly governed by the amount and molecular weight of 1,2,3-triacylglyceride units. Figure 4 shows a plot of the weight-average molecular weight of polyester resins versus the relative molar ratio of 1-acylglycerides, where the ratio decreases with increasing molecular weight. Figure 5 shows a plot of the weight-average molecular weight of polyester resins versus the relative molar ratio of 1,2,3-triacylglycerides, where the ratio decreases with increasing molecular weight.

[0238] Example 5

[0288] Using size exclusion chromatography-refractive index multi-angle light scattering (SEC-RI-MALS), the molecular weight of the PG:Seb polyester resin was measured at various points in time during polycondensation synthesis, and the molecular weight was obtained by comparing it with a PS standard using an RI detector.

[0239] Example 6

[0289] Radar plots were created to show nine different physicochemical parameters for various selected polyester-urethane formulations. The nine parameters represent the M of polyester in Da. w The parameters included the polydispersity index of polyester, the molar percentage of 1,2,3-acylglycerides in polyester, the average solubility of diacids in mg / mL, the average diacid hydrocarbon length (average number of CH2 groups between carboxylic acids), the hydroxyl value of polyester in mgKOH / g, the acid value of polyester in mgKOH / g, the rotational flow viscosity of polyester in Pa·s, and the log(P) value of isocyanate.

[0240]

[0290] Figure 6 shows radar plots of polyester urethanes having polyester components formed from polyesters of various molecular weights. The polyester components consisted of a single polyol, specifically glycerol, and one or more polyacids, specifically sebacic acid, adipic acid, or copolymers of adipic acid:sebacic acid or succinic acid:sebacic acid. The polyester components were synthesized using either a polyol:polyacid molar ratio of 1:1 or 1.1:1. The urethane components consisted of either HDI or LDI. The radar plots show physicochemical parameters on each radial axis, with values ​​ranging from 0 at the center to the maximum value displayed for each axis.

[0241]

[0291] Figure 7 shows radar plots of PGSU formulations prepared using polyesters with a polyol:polyacid molar ratio of either 1:1 (circles) or 1.1:1 (downward triangles), and using either HDI (solid line) or LDI (dashed line).

[0242]

[0292] Figure 8 shows radar plots of PGSU formulations prepared using polyesters with a polyol:polyacid molar ratio of either 1:1 (circles) or 1.1:1 (downward triangles), and prepared using HDI.

[0243]

[0293] Figure 9 shows radar plots of PGSU formulations prepared using polyesters with a polyol:polyacid molar ratio of either 1:1 (circles) or 1.1:1 (downward triangles), and prepared using LDI.

[0244]

[0294] Figure 10 shows radar plots of PGSU formulations prepared using polyesters with adipic acid (circles) or succinic acid (horizontal triangles) and sebacic acid, and using HDI. The polyacid copolymers of adipic acid:sebacic acid or succinic acid:sebacic acid had a molar ratio of 50:50. The polyesters were synthesized using a polyol:polyacid molar ratio of 1:1.

[0245]

[0295] Figure 11 shows radar plots of PGSU formulations prepared using either adipic acid (white circles) or a polyacid copolymer of adipic acid and sebaciate in molar ratios of 50:50 (light gray circles) or 25:75 (dark gray circles), and prepared using HDI. The polyesters were synthesized using a polyol:polyacid molar ratio of 1:1.

[0246]

[0296] Figure 12 shows radar plots of PGSU formulations prepared using either adipic acid (white marker) or sebacic acid (gray marker) polyesters with a polyol:polyacid molar ratio of 1:1 (circles) or 1.1:1 (downward triangles), and prepared using HDI.

[0247] Example 7

[0297] For grafts of non-supported polyester urethanes crosslinked by HDI, degradation profiles were obtained under accelerated degradation conditions of 70 °C in 0.1 M PBS. The polyester resins had various polyol:polyacid molar ratios, molecular weights, diacid components, and / or presence of free acid for comparison with conventional PGSU(1-HDI). The grafts were cylindrical with a diameter of 5 mm and a height of 5 mm. At each time point, three samples of each polyester urethane were washed with deionized water, dried under vacuum at 40 °C for 48 hours, and then weighed. The mass % results are shown in Table 4, indicating that a wide range of degradation rates is possible when using HDI as the crosslinking agent without changing the crosslinking agent to polyester ratio.

[0248]

Table 4

[0249]

[0298] The polyester urethane 14-HDI containing adipic acid completely degraded in just 3.26 weeks, which is 5 times faster than conventional PGSU. Unexpectedly, the polyester urethane 4-HDI containing succinic acid degraded at a slower rate than the adipic acid-containing equivalent despite having a shorter diacid, but this 3.42 weeks was still 4 times faster than the time it takes for conventional PGSU to completely degrade.

[0250] Example 8

[0299] For grafts of non-supported polyester urethanes crosslinked by HDI, degradation profiles were obtained under the same experimental procedure as in Example 7. The polyester resins had various polyol:polyacid molar ratios, molecular weights, and / or diacid components. Results for conventional PGSU 1-HDI are included for reference. The 4-week results in mass % are shown in Table 5, indicating that a wide range of degradation rates is possible when using LDI as the crosslinking agent without changing the crosslinking agent to polyester ratio.

[0251]

Table 5

[0252]

[0300] Polyester urethane 11-LDI containing only adipic acid decomposed completely in just 3.26 weeks, which is 5 times faster than conventional PGSU. Polyester urethane 14-LDI containing both sebaciic acid and adipic acid decomposed completely in just 2.86 weeks. Polyester urethane 4-LDI containing both sebaciic acid and succinic acid decomposed completely in just 2.57 weeks.

[0253] Example 9

[0301] Degradation profiles were obtained for unsupported polyester urethane grafts containing various ratios of sebaciic acid and adipic acid under the same experimental procedure as in Example 7. For reference, results for conventional PGSU are included. The results in mass percent are shown in Table 6.

[0254] [Table 6]

[0255]

[0302] Table 6 shows that the polymer degradation profile can be adjusted by controlling the adipic acid content from 0 to 50%. Unexpectedly, the construct with 95% adipic acid degraded slightly more slowly than the equivalent construct with 50% adipic acid, suggesting ideal tunability.

[0256] Example 10

[0303] Decomposition times at 70°C were obtained for unsupported polyester urethane grafts containing various ratios of sebaciic acid and adipic acid, under the same experimental procedure as in Example 7. For reference, results for conventional PGSU are included. The results when HDI was used as the crosslinking agent are plotted in Figure 13 as decomposition time per week versus the molecular weight of the polyester resin. The results when LDI was used as the crosslinking agent are plotted in Figure 14 as decomposition time per week versus the molecular weight of the polyester resin. Figure 15 shows the decomposition versus crosslink density at week 4 for various LDI-crosslinked polyester urethanes compared with 1-HDI.

[0257] Example 11

[0304] Degradation profiles were obtained for polyester urethane grafts doped with either free acid, tartaric acid (TA), citric acid (CA), lactic acid (LA), or acetic acid (AA), under the same experimental procedure as in Example 7. For reference, results for conventional PGSU are included. The prepolymer was mixed with the free acid before crosslinking. The amount of free acid is expressed as a weight percentage. Results in mass percent are shown in Table 7. Figure 16 shows the degradation versus the crosslinking density of these polyester urethanes at week 4.

[0258] [Table 7]

[0259]

[0305] Table 7 shows that the addition of tartaric acid resulted in significantly higher decomposition rates compared to other acids at equivalent wt%. Surprisingly, no adverse effects on crosslink density were observed at these amounts, but as expected, hydrolysis was enhanced by the addition of the acid. Higher wt% of tartaric acid did not result in faster decomposition rates and, in some cases, caused excessive bubbles within the graft. Free acids such as tartaric acid act as catalysts for the hydrolysis of ester bonds, leading to a significantly larger hydrolyzable polymer network.

[0260] Example 12

[0306] Degradation profiles were obtained for polyester urethane grafts containing adipic acid and sebacic acid, either doped with TA or undoped, under the same experimental procedure as in Example 7. For reference, results for conventional PGSU are included. The polyester resin was mixed with free acid before crosslinking. The amount of free acid added is in weight percent. The results in mass percent are shown in Table 8.

[0261] [Table 8]

[0262]

[0307] Table 8 shows that the addition of 0.1% free tartaric acid provided a similarly significant increase in the degradation rate of polyester urethanes containing adipic acid and sebacic acid, as did the significant increase for conventional PGSU.

[0263] Example 13

[0308] The degradation of unsupported polyester urethane crosslinked with HDI was measured at 4 weeks. Figure 17 shows a plot of crosslink density against degradation percentage after 4 weeks. Even at very high crosslink densities (8-HDI), PGAdU degraded significantly faster than PGSU(1-HDI), which was unexpected. Figure 18 shows that a wide range of degradation rates can be achieved without significantly altering the crosslink density by using a mixture of crosslinking agents.

[0264] Example 14

[0309] The sol content (Q, %) was determined for a specific polyester urethane rod measuring 3 mm x 40 mm at room temperature in THF for 24 hours. Figure 19 shows that the sol content for polyester 1 increases when the crosslinking agent is changed from HDI to LDI and 12DI. It is presumed that the decrease in crosslinking density of LDI and 12DI formulations causes this effect. A similar effect is observed when formulations made using polyester 7 are used. A lower sol content suggests the presence of lower levels of extractable material in the formulation.

[0265] Example 15

[0310] During accelerated 70°C decomposition studies, 7-HDI broke down into increasingly smaller and larger fragments over time. In contrast, pre-vacuum PGS (resin 21), which has a low molecular weight, and 21-HDI collected before the vacuum step during polycondensation, remained as a single fragment throughout the overall mass and diameter loss over time. The mechanism of decomposition can play a significant role in product performance and patient acceptability. For example, in the case of intravitreal grafts, decomposition of the graft into multiple fragments is undesirable, as it can lead to problems with vision, lymphatic drainage, lacrimal drainage, inflammation, and foreign body response, among other negative physiological effects.

[0266] Example 16

[0311] Degradation profiles were obtained for polyester urethane grafts formed from a blend of two polyester resins under the same experimental procedure as in Example 7. For reference, results for conventional PGSU are included. The polyester resins were blended together in equal amounts by weight overnight before crosslinking. The results in mass% are shown in Table 9.

[0267] [Table 9]

[0268]

[0312] As shown in Table 9, Ad:Seb resins blended more uniformly with PGS than conventional PGSU, resulting in a more homogeneous and faster-degrading urethane elastomer. Suc:Seb resins showed some signs of demixing and phase separation with PGS resins during blending, as indicated by their mass loss profiles and degradation topography, and degraded heterogeneously after urethane crosslinking.

[0269] Example 17

[0313] Decomposition profiles were obtained for polyester urethane grafts formed using various HDI:LDI ratios, under the same experimental procedure as in Example 7. For reference, results for conventional PGSU are included. Results in mass percent are shown in Table 10.

[0270] [Table 10]

[0271]

[0314] Table 10 shows that the degradation kinetics of polyester urethane can be regulated by using more soluble crosslinking agents, such as LDI, in combination with HDI. This effect is closely related to the difference in molecular weight of the degradation products formed using various crosslinking agents.

[0272] Example 18

[0315] Degradation profiles were obtained for polyester urethane grafts formed using diacids other than sebaciate and / or crosslinking agents other than HDI, under the same experimental procedure as in Example 7. For reference, results for conventional PGSU are included. Results in mass percent are shown in Table 11.

[0273] [Table 11]

[0274]

[0316] Table 11 shows that the degradation kinetics of polyester urethanes with glycerol:diacid ratios other than the conventional 1:1 can be adjusted using more soluble crosslinking agents such as LDI.

[0275] Example 19

[0317] Degradation profiles were obtained for polyester urethane grafts formed using a diacid mixture of sebaciic acid and adipic acid or succinic acid, and a crosslinking agent of HDI or LDI, under the same experimental procedure as in Example 7. For reference, results for conventional PGSU are included. Results in mass percent are shown in Table 12.

[0276] [Table 12]

[0277]

[0318] Table 12 shows that the degradation advantage of LDI over HDI is greater in some polymer formulations than in others, depending on the composition of the soft segment. Ad:Seb polyester urethane had very similar degradation profiles when using two different crosslinking agents, whereas Suc:Seb polyester urethane had a significantly faster degradation profile when using LDI than when using HDI.

[0278] Example 20

[0319] Decomposition profiles were obtained for polyester urethane grafts formed using sebaciic acid or adipic acid as the diacid and HDI or LDI as a crosslinking agent, under the same experimental procedure as in Example 7, except that they were molded to a diameter of 3 mm and a length of 10 mm and decomposed at a temperature of 37°C. Furthermore, the diameter was measured at weeks 8 and 16, and the diameter loss was calculated. For reference, results for conventional PGSU are included. The mass loss results are shown in Figure 20A. The diameter loss results are shown in Figure 20B.

[0279]

[0320] 7-HDI and 7-LDI showed significant swelling during decomposition at 37°C, where the original 3 mm grafts swelled to 3.4 mm and 3.9 mm, respectively, by week 16. Upon drying, 7-LDI showed a diameter loss of 340 μm, while 7-HDI showed a diameter loss of only 50 μm. In contrast, 1-LDI showed less swelling than 7-LDI but exhibited similar diameter losses of approximately 200 μm at week 8 and approximately 260 μm at week 16. At week 16, 7-LDI showed the greatest mass loss, followed by 7-HDI, and then 1-LDI. However, 1-LDI was the only one whose mass loss and diameter loss were better synchronized with surface erosion as a decomposition mechanism.

[0280]

[0321] Mass loss and dimensional loss data at 37°C support the findings at 70°C, indicating that the incorporation of adipic acid increases the degradation rate of polyester urethane compared to conventional PGSU. The degradation rate can also be adjusted by changing the hydrophilicity of the crosslinks from the most hydrophobic 12DI to the most hydrophilic LDI.

[0281] Example 21

[0322] P[1.1:1]G:[50:50]Suc:Seb (resin 22) was also dialyzed to P[1.1:1]G:[50:50]Suc:seb[D] (resin 23) for similar purposes. The hydroxyl value decreased from 262 to 215 mgKOH / g. Interestingly, the acid value remained the same at 55 mgKOH / g. The yield after dialyzation was approximately 70–85 wt%. In the case of the intentionally reduced hydroxyl value after hydrolysis, in contrast to the example of P[1.1:1]G:Ad-HDI, the isocyanate content that needed to be added to the formulation to maintain equivalent stoichiometric equivalents of isocyanate to hydroxyl was not very large. Nevertheless, despite having only slightly higher crosslinking due to Florey-Löner swelling of 1.725 mol / L versus 1.377 mol / L, the dialyzed 17-HDI formulation degraded more slowly than the 14-HDI formulation. Furthermore, dialyzed 17-HDI degraded faster than undialyzed 16-HDI, despite having a higher resin molecular weight, although it had a lower crosslinking density of 1.725 mol / L compared to 2.516 mol / L. Additionally, dialyzed 17-HDI sustained release better than 14-HDI. These results, taken together, suggest the importance of the polyol:polyacid stoichiometric ratio of 1:1 versus 1.1:1, as well as the influence of hydroxyl groups, carboxylates, and monomers and oligomers in the initial polymer resin.

[0282] Example 22

[0323] Figure 21 shows the degradation profile for the tested grafts of the target polyester urethane. Figure 22 shows the degradation profile for the tested grafts of further target polyester urethane. For reference, results for conventional PGSU are included. This group includes various polyester resins with varying molecular weights, sebacic acid, adipic acid, or a combination of the two as diacids, and polyester resin blends with HDI or LDI as crosslinking agents, and several doped with free acids.

[0283]

[0324] Polymers in this range highlight the effects of using various diacids, diacid-to-glycerol ratios, crosslinkers, and prepolymer molecular weights in shaping the degradation profile of polyester urethanes over a wide timeframe.

[0284] Example 23

[0325] The polyester resin of Example 1 was crosslinked using either HDI or LDI. The resulting polyester urethane grafts were subjected to degradation in 0.1 M PBS under accelerated degradation conditions at 70°C, compared to conventional PGSU(1-HDI). The grafts were cylindrical with a diameter of 5 mm and a height of 5 mm. The weight-average molecular weight and number-average molecular weight of the degradation products were determined using SEC spectra. w M n The PDI values ​​are assigned to Table 13.

[0285] [Table 13]

[0286]

[0326] Polyester urethane using LDI as a crosslinking agent has a significantly higher M than that using HDI as a crosslinking agent, except for LDI where adipic acid is the only diacid. w It had a value. In that case, M w The values ​​were similar to those of polyester urethane using HDI as a crosslinking agent. w M nThe increase in PDI values ​​indicates increased solubility of larger degradation products, while small to medium-sized soluble degradation products are still present even when large soluble degradation products are available.

[0287] Example 24

[0327] The swelling rates of certain unsupported polyester urethanes were determined in both THF and water, and their hydrophilicity was evaluated. These polymers included polyester resins containing both glycerol and 300 g / mol polyethylene glycol (PEG300) as polyols, thereby allowing for adjustment of the polymer's hydrophilicity. The results for THF after 24 hours at room temperature are shown in Figure 23, and for water after 7 days at room temperature are shown in Figure 25. Polyester urethanes containing PEG300 showed higher water uptake over 7 days compared to the base glycerol polymer formulation. Furthermore, a significant increase in water uptake was observed when switching from P[0.75:0.25:1]G:PEG300:Seb to P[0.75:0.25:1]G:PEG300:Ad, indicating that the type of diacid used in the polyester resin also strongly influences water uptake.

[0288]

[0328] Table 14 and Figure 24 show the further swelling results of polyester urethane in THF after 24 hours at room temperature.

[0289] [Table 14]

[0290]

[0329] Figure 26 shows the swelling results in water for further polyester polyurethane after 7 days at room temperature. Figure 27 shows the water absorption of a specific polyester polyurethane after 1 day and 7 days at room temperature.

[0291]

[0330] The crosslinking density of polyester urethanes was determined by Florey-Lenner solvent swelling in THF. The bar for conventional PGSU (1(30L scale)-HDI derived from resin 1 prepared on a 30L scale) is black. The bar for HDI crosslinked polymers, including 1(10L scale)-HDI derived from resin 1 prepared on a 10L scale with a crosslinking density similar to 1(30L scale)-HDI, is gray. The bar for LDI crosslinked polymers is white. The bar graph for crosslinking agent combinations is a grid pattern. These included combinations of HDI, LDI, or 12DI. Several polyester urethanes contained acid additives at either 0.1% or 1%. These additives included acetic acid (AA), tartaric acid (TA), citric acid (CA), and lactic acid (LA). The results are shown in Figure 28.

[0292]

[0331] Equivalent isocyanate-to-hydroxyl group ratios of 1:1 to 1.1:1 were applied to the 1-LDI and 1-HDI formulations. Unexpectedly, 1-LDI had a lower crosslinking density of approximately 1 mol / L for the bulk network compared to approximately 2 mol / L for 1-HDI, when examined by Florey-Löner solvent swelling. The graft samples examined were from the same batch as those described in Example 20.

[0293]

[0332] The stoichiometric ratio of glycerol:adipic acid is 1.1:1 and M wP[1.1:1]G:Ad(5k)-HDI (polyester resin 11), synthesized at approximately 5,000 Da, was compounded using either LDI or HDI with equivalent isocyanate-to-hydroxyl ratios of 1:1 to 1.1:1. 11-LDI exhibited a higher crosslinking density in the bulk network compared to 1-LDI, 1-HDI, or 18-HDI, as examined by Florey-Löner solvent swelling. 11-HDI showed the highest crosslinking density of all compounds, significantly higher than that crosslinked using LDI, as examined by Florey-Löner solvent swelling. The crosslinking densities empirically measured by Florey-Löner solvent swelling do not predict the degradation time in these formulations. Polyester resin 11 compounded with either LDI or HDI showed crosslinking densities higher than 2.5 times or 3.5 times, respectively, with solvent swelling, but degraded significantly faster than 1-HDI.

[0294]

[0333] The high hydroxyl value of polyester resin 11 was adapted during formulation by increasing the isocyanate to maintain a stoichiometrically equivalent ratio. This resulted in a very dense crosslinked network that was not swellable, but it decomposed unexpectedly more rapidly, due to the soft segment polyacid composition. This may be due to the polyglycerol adipate region being more impermeable to THF, the solvent in which the swelling experiments are performed (see also Godinho et al.). This was consistent with what was observed when using polymers similarly prepared with succinic acid. However, the rate of decomposition in water-based media was unexpected, suggesting that swelling and crosslinking in the semipolar solvent THF do not necessarily correlate with polymer behavior in water. It is very interesting that the effects expected with thermosetting resins are likely to be similar even when the resin is crosslinked with isocyanate.

[0295]

[0334] Furthermore, the release of dexamethasone supported in polyester urethane was unexpectedly faster than in other formulations with lower crosslinking densities, similarly due to the flexible segment polyacid composition. Figure 29 shows that 1-LDI exhibits a lower degree of crosslinking than 1-HDI, and therefore faster degradation is expected, but its more persistent release of dexamethasone was unexpected (see Example 32 and Figure 33). These results suggest the importance of microstructure, which is more important than considering only the isocyanate-to-hydroxyl group ratio or crosslinking density to predict performance.

[0296] Example 25

[0335] 10% 1,4-butanediol was added as a chain extender to 30% by weight hydrophilic 2'-deoxyadenosine-supported 1-HDI. 100% of 2'-deoxyadenosine was released within 14 days in simulated gastric juice (SGF) at pH 1.2 at 37°C, compared to 28 days for 100% release of 2'-deoxyadenosine from solvent-free 1-HDI under the same conditions without the chain extender. 1-HDI with 10% 1,4-butanediol became a resinous material after 2 weeks at pH 1.2 and 37°C, losing 38% of its polymer mass and all mechanical integrity, in contrast to solvent-free 1-HDI which took more than 12 weeks.

[0297] Example 26

[0336] In one example, a 15% mass loss was observed in 10% hydrophilic API-supported 1-HDI with 10% 1,4-butanediol after 21 days, in contrast to the negligible mass loss in solvent-free 1-HDI.

[0298] Example 27

[0337] In one example, 1-HDI supported by 30% by weight of 2'-deoxyadenosine with 5% by weight, 7.5% by weight, and 10% by weight of 1,5-pentanediol showed polymer mass losses of 6%, 10%, and 10% by day 7 in SGF at pH 1.2 and 37°C. 1-HDI supported by 30% by weight of 2'-deoxyadenosine with 5% by weight, 7.5% by weight, and 10% by weight of 1,5-pentanediol showed polymer mass losses of 9%, 12%, and 13% by day 21 in SGF at pH 1.2 and 37°C. Polymer mass loss leveled off after day 21. Since the isocyanate is added after the chain extender is added to the polyester resin, a reaction may occur between the isocyanate and the chain extender. This reduces crosslinking of the polyester resin by the isocyanate, and the final PGSU may have phase separation regions with chain extender-isocyanate repeating units. When exposed to aqueous release media such as SGF, these isocyanate-chain extender units can be rapidly lost, which corresponds to a rapid mass loss in the first few weeks. After this rapid initial loss, the remaining PGSU has a longer degradation time.

[0299] Example 28

[0338] Microdevices made of polyester urethane supported with 60 wt% dexamethasone were analyzed for mass loss by extraction at 1, 6, 9, and 12 months in a release / degradation study in PBS / saline at 37°C and 50 RPM. The microdevices were cylindrical in shape with a diameter of 450 μm and a length of 10 mm. For extraction, the samples were extracted in dimethyl sulfoxide at room temperature for 4 hours / 400 RPM. The extraction medium was diluted 1:10 in acetonitrile:Type 1 water 50:50 and processed by HPLC by passing it through an Agilent Zorbax C18 reverse-phase column for the detection of dexamethasone, along with a DMSO blank and a 0.5 mg / mL dexamethasone control. Dexamethasone concentrations were calculated based on the dexamethasone standard curve (R 2(=0.9999), the initial dexamethasone load was examined and used to quantify total drug release. Using the post-release mass of the washed and lyophilized microrods, the mass % loss contributing to polymer degradation was calculated by simply subtracting the amount of dexamethasone released. The mass loss was attributed only to the polyester urethane content. Faster hydrolysis of the shorter diacitors was observed even in the presence of dexamethasone. The results are shown in Table 15.

[0300] [Table 15]

[0301]

[0339] Table 15 shows that polyester urethanes using adipic acid as the polyacid decomposed faster than those using sebaciic acid, highlighting the effect of esterification frequency within the polyol despite equivalent isocyanate-to-hydroxyl group stoichiometric ratios. Polyester urethanes using LDI as the isocyanate decomposed faster than those using HDI. Furthermore, sebaciic acid-based polyols with low molecular weights, such as 18-HDI and 19-HDI, showed faster initial mass loss for 3–9 months when compounded with polyester urethanes, due to the solubilization of shorter chains. However, long-term decomposition at 12 months revealed that compoundings using higher molecular weight polyols outperformed lower molecular weight polyols in terms of mass loss. This effect is attributed to the microstructure of lower molecular weight polyol chains compared to the amorphous structure of higher molecular weight polyols. Subsequently, hydrophobic HDI crosslinkers can stabilize the polyol microstructure through the formation of urethane bonds, resulting in the observed characteristic decomposition behavior.

[0302] Example 29

[0340] Two microdevices from Example 28 were imaged by SEM before degradation study and after a 3-month degradation study following freeze-drying. Figure 30A shows 7-HDI before degradation study. Figure 30B shows 7-HDI after degradation study and freeze-drying. Figure 31A shows 18-HDI before degradation study. Figure 31B shows 18-HDI after degradation study and freeze-drying.

[0303]

[0341] Larger pores in the 18-HDI formulation after 3 months may contribute to a higher degree of dexamethasone aggregation during the compounding / curing process. Although differences are observed between the two formulations, freeze-drying may have caused pore collapse, accompanied by more degradation of the polyester urethane or softer mechanical properties.

[0304] Example 30

[0342] Dexamethasone was well distributed in PGSU(1-HDI) at t=0, and no large pores were observed during drug elimination as the drug was released at 37°C. In contrast, dexamethasone acetate supported on 1-HDI left large pores during drug elimination. This may be due to dexamethasone acetate being more hydrophobic and having a distribution coefficient log(P) 2.6 compared to dexamethasone with a log(P) of 1.93. Dexamethasone has a solubility of approximately 75 μg / mL, while dexamethasone acetate has a lower water solubility of approximately 5 μg / mL in PBS at 25°C.

[0305] Example 31

[0343] In another example, dexamethasone was well distributed in 1-LDI at t=0, and no large pores were observed during drug elimination, as the drug was released at 37°C. In contrast, dexamethasone supported on low molecular weight, low branching 1-HDI left large pores during drug elimination. This may be due to differences in the behavior of dexamethasone in two different soft segments and / or two different hard segments. The log(P) of HDI is 0.89, while the log(P) of LDI is 0.76. Drug release, mass loss, diameter loss, and surface roughness were nearly similar between the two formulations at 3 months, but may show differences at subsequent time points. Both formulations showed a diameter loss of 100 μm from their original diameter, measured at 3 months after drying of the sample, but 1-LDI showed a larger swelling diameter at 3 months.

[0306] Example 32

[0344] The cumulative release profile was measured for polyester urethane microdevices supported with 60% by weight of dexamethasone, similar to the profile of Example 28 (n=9 for each formulation). Dexamethasone release was evaluated in 100 mL of PBS or physiological saline (3x sink conditions) at 37°C / 50 RPM, with sampling on day 3 or 4, followed by complete medium change weekly. The release medium was analyzed for dexamethasone by HPLC using an Agilent 1260 Infinity II system equipped with an Agilent Zorbax C18 reversed-phase column, and the concentration was calculated using the dexamethasone standard curve (R 2 (=0.9999). The mobile phase included gradients of Type 1 with 0.1% formic acid and HPLC-grade acetonitrile with 0.1% formic acid at a flow rate of 1 mL / min. Cumulative release was calculated by converting the release concentration to the released mass and dividing by the total initial mass of dexamethasone. Figure 32 shows the obtained release profiles. 7-HDI provided the fastest release, significantly faster than the other five polyester urethanes using sebacic acid as the polyacid.

[0307]

[0345] Figure 33 shows five polyester urethanes using sebacic acid alone. The use of LDI as a crosslinking agent with high molecular weight PGS resins resulted in a slower release kinetics, as can be seen by comparing the curves for 1-HDI and 1-LDI. When HDI was replaced with LDI for low molecular weight PGS resins, the release kinetics were accelerated instead, as can be seen by comparing 18-HDI or 19-HDI with 18-LDI. Surprisingly, this effect was not observed when different forms of dexamethasone with smaller particle sizes and less aggregation were supported, where the HDI type decomposed / released faster than the LDI type, demonstrating a dependence on the morphology and arrangement of the API within the polymer.

[0308] Example 33

[0346] The cumulative release profile was measured for a polyester urethane microdevice supported with 60 wt% dexamethasone, similar to the profile in Example 32, following a procedure similar to that of Example 32. Figure 34 shows the obtained release profile. These examples highlight the ability to adjust the release rate of hydrophobic molecules using the adipic acid:sebacic acid ratio.

[0309]

[0347] All of the above references are incorporated herein by reference.

[0310]

[0348] While the present invention has been described with reference to one or more exemplary embodiments, it will be understood by those skilled in the art that various modifications may be made without departing the scope of the invention, and its elements may be substituted with equivalents. Furthermore, many modifications may be made to adapt the teachings of the invention to specific situations or materials without departing the essential scope of the invention. Accordingly, the present invention is not limited to the specific embodiments disclosed as the best mode considered for carrying out the invention, but is intended to encompass all embodiments that fall within the scope of the accompanying claims. Furthermore, all numerical values ​​specified in the detailed description should be interpreted as both exact and approximate values ​​being explicitly specified.

Claims

1. A composition comprising polyester urethane, wherein the polyester urethane comprises a diisocyanate-based crosslinking agent and an alternating copolymer resin of at least one polyol monomer and at least one polyacid monomer, the crosslinking agent crosslinks the alternating copolymer resin, the alternating copolymer resin has a degree of branching, weight-average molecular weight, polydispersity index, and viscosity before crosslinking, the polyester urethane has a first stoichiometric ratio of at least one polyol to at least one polyacid, the polyester urethane has a second stoichiometric ratio of isocyanate to hydroxyl, and the polyester urethane comprises a rigid segment of the crosslinking agent and the alternating copolymer resin. A composition having a phase separation microstructure between a soft segment of a copolymer resin, wherein the crosslinking stabilizes the phase separation microstructure, and the phase separation microstructure provides the composition with predetermined properties selected from the group consisting of decomposition rate in an aqueous environment, release rate of a drug supported in the polyester urethane in an aqueous environment, solubility of the drug, and combinations thereof.

2. The composition according to claim 1, wherein the at least one polyol monomer comprises glycerol.

3. The composition according to claim 1, wherein the at least one polyacid monomer is selected from the group consisting of sebacic acid, suberic acid, adipic acid, succinic acid, and combinations thereof.

4. The composition according to claim 1, wherein the diisocyanate is selected from the group consisting of hexamethylene diisocyanate and lysine diisocyanate.

5. The composition according to claim 4, wherein the weight-average molecular weight of the alternating copolymer resin is less than 6,500 Da.

6. The composition according to claim 4, wherein the degree of branching is such that the polyester resin has a 1,2,3-triacylglyceride content of less than 15 mol%.

7. The composition according to claim 4, wherein the degree of branching is such that the polyester resin has a 1,2,3-triacylglyceride content of more than 15 mol% or equal to that amount, and the isocyanate comprises lysine diisocyanate.

8. The composition according to claim 1, wherein the at least one polyol monomer comprises glycerol, the at least one polyacid comprises sebaciic acid, and the isocyanate comprises lysine diisocyanate.

9. The composition according to claim 8, wherein the at least one polyacid monomer further comprises adipic acid.

10. The composition according to claim 1, further comprising a chain extender selected from the group consisting of 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, isopentyldiol, 2-methyl-1,3-propanediol, bis(2-hydroxyethyl)terephthalate, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, ethylenediamine, 2-hydroxyethyl 2-hydroxypropanoate, and 2,2-bis(hydroxymethyl)propionic acid.

11. The composition according to claim 10, wherein the chain extender is added in an amount of about 5 to 15% by weight relative to the weight of the fluid polyester resin.

12. The composition according to claim 1, comprising the drug.

13. A method for forming polyester urethane, A step of selecting at least one polyol monomer, at least one polyacid monomer, and a diisocyanate, The steps include combining the at least one polyol monomer and the aqueous liquid in a container, The steps include selecting a first stoichiometric ratio of the at least one polyol monomer to the at least one polyacid monomer, and adding the at least one polyacid monomer to the container in the first stoichiometric ratio. The steps include removing water from the container, A step of producing an alternating copolymer resin of at least one polyol monomer and at least one polyacid monomer, wherein the alternating copolymer resin has a degree of branching, a weight-average molecular weight, a polydispersity index, and a viscosity, The steps include selecting a second stoichiometric ratio of isocyanate to hydroxyl, and homogeneously combining a fluid blend containing the alternating copolymer resin in the second stoichiometric ratio with the diisocyanate to form the polyester urethane. Includes, A method wherein the at least one polyol monomer, the at least one polyacid monomer, the diisocyanate, the first stoichiometric ratio, the second stoichiometric ratio, the degree of branching, the weight-average molecular weight, the polydispersity index, and the viscosity are selected to form a phase separation microstructure between the rigid segment of the crosslinking agent and the soft segment of the alternating copolymer resin, wherein the phase separation microstructure provides a predetermined property selected from the group consisting of the decomposition rate in an aqueous environment, the release rate of a drug supported in the polyester urethane in an aqueous environment, the solubility of the drug, and combinations thereof.

14. The method according to claim 13, further comprising the steps of selecting a drug and selecting a timing for adding the drug, selected from the group consisting of adding it to the alternating copolymer resin, adding it to the fluid blend, and adding it to the diisocyanate, wherein the at least one polyol monomer, the at least one polyacid monomer, the diisocyanate, the first stoichiometric ratio, the second stoichiometric ratio, and the timing of the addition are selected to form the polyester urethane on which the drug is supported having the release rate of the drug in the aqueous environment.

15. The method according to claim 13, wherein the at least one polyol monomer comprises glycerol.

16. The method according to claim 13, wherein the at least one polyacid monomer is selected from the group consisting of sebacic acid, suberic acid, adipic acid, succinic acid, and combinations thereof.

17. The method according to claim 13, wherein the diisocyanate is selected from the group consisting of hexamethylene diisocyanate and lysine diisocyanate.

18. The method according to claim 17, wherein the weight-average molecular weight of the alternating copolymer resin is less than 6,500 Da.

19. The method according to claim 17, wherein the degree of branching is such that the polyester resin has a 1,2,3-triacylglyceride content of less than 15 mol%.

20. The method according to claim 17, wherein the degree of branching is such that the polyester resin has a 1,2,3-triacylglyceride content greater than or equal to 15 mol%, and the isocyanate comprises lysine diisocyanate.

21. The method according to claim 13, wherein the at least one polyol monomer comprises glycerol, the at least one polyacid comprises sebaciic acid, and the isocyanate comprises lysine diisocyanate.

22. The method according to claim 21, wherein the at least one polyacid monomer further comprises adipic acid.

23. The method according to claim 13, further comprising the step of adding a chain extender selected from the group consisting of 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, isopentyldiol, 2-methyl-1,3-propanediol, bis(2-hydroxyethyl)terephthalate, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, ethylenediamine, 2-hydroxyethyl 2-hydroxypropanoate, and 2,2-bis(hydroxymethyl)propionic acid.

24. The method according to claim 23, wherein the chain extender is added in an amount of about 5 to 15% by weight relative to the weight of the fluid polyester resin.

25. A transplantable product comprising a drug and a polyester urethane, wherein the polyester urethane comprises a diisocyanate-based crosslinking agent and an alternating copolymer resin of at least one polyol monomer and at least one polyacid monomer, the crosslinking agent crosslinks the alternating copolymer resin, the alternating copolymer resin has a degree of branching, weight-average molecular weight, polydispersity index, and viscosity before crosslinking, the polyester urethane has a first stoichiometric ratio of the at least one polyol to the at least one polyacid, the polyester urethane has a second stoichiometric ratio of isocyanate to hydroxyl, and the polyester urethane comprises a rigid segment of the crosslinking agent and A transplantable product having a phase separation microstructure between the soft segments of the alternating copolymer resin, wherein the crosslinking stabilizes the phase separation microstructure, and the phase separation microstructure provides the composition with predetermined properties selected from the group consisting of decomposition rate in an aqueous environment, release rate of a drug supported in the polyester urethane in an aqueous environment, solubility of the drug, and combinations thereof.

26. The implantable product according to claim 25, wherein the at least one polyol monomer comprises glycerol.

27. The transplantable product according to claim 25, wherein the at least one polyacid monomer is selected from the group consisting of sebacic acid, suberic acid, adipic acid, succinic acid, and combinations thereof.

28. The transplantable product according to claim 25, wherein the diisocyanate is selected from the group consisting of hexamethylene diisocyanate and lysine diisocyanate.

29. The implantable product according to claim 28, wherein the weight-average molecular weight of the alternating copolymer resin is less than 6,500 Da.

30. The transplantable product according to claim 28, wherein the degree of branching is such that the polyester resin has a 1,2,3-triacylglyceride content of less than 15 mol%.

31. The transplantable product according to claim 28, wherein the degree of branching is such that the polyester resin has a 1,2,3-triacylglyceride content greater than or equal to 15 mol%, and the isocyanate comprises lysine diisocyanate.

32. The implantable product according to claim 25, wherein the at least one polyol monomer comprises glycerol, the at least one polyacid comprises sebaciic acid, and the isocyanate comprises lysine diisocyanate.

33. The transplantable product according to claim 32, wherein the at least one polyacid monomer further comprises adipic acid.

34. The implantable product according to claim 25, further comprising a chain extender selected from the group consisting of 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, isopentyldiol, 2-methyl-1,3-propanediol, bis(2-hydroxyethyl)terephthalate, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, ethylenediamine, 2-hydroxyethyl 2-hydroxypropanoate, and 2,2-bis(hydroxymethyl)propionic acid.

35. The transplantable product according to claim 34, wherein the chain extender is added in an amount of about 5 to 15% by weight relative to the weight of the fluid polyester resin.

Images