Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G18/00—Polymeric products of isocyanates or isothiocyanates
  • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
  • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
  • C08G18/72—Polyisocyanates or polyisothiocyanates
  • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
  • C08G18/75—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic
  • C08G18/758—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing two or more cycloaliphatic rings
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G18/00—Polymeric products of isocyanates or isothiocyanates
  • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
  • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
  • C08G18/40—High-molecular-weight compounds
  • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
  • C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
  • C08G18/428—Lactides
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G2230/00—Compositions for preparing biodegradable polymers

Definitions

• the present embodiment relates to biodegradable and/or bioabsorbable polymers and finds particular application in connection with a process for making such compounds.
• biodegradable and/or bioabsorbable materials are implants, such as screws, pins, bone plates, staples, sutures (monofilament and multifilament), drug-delivery vehicles, membranes for guided tissue regeneration, mesh and porous materials for tissue engineering, anti-adhesion barriers, tissue scaffolds, cardiovascular grafts, and wound dressings.
• implants such as screws, pins, bone plates, staples, sutures (monofilament and multifilament), drug-delivery vehicles, membranes for guided tissue regeneration, mesh and porous materials for tissue engineering, anti-adhesion barriers, tissue scaffolds, cardiovascular grafts, and wound dressings.
• biodegradable and/or bioabsorbable polymers to meet a variety of applications where the desired combination of physical properties and degradation rate can be chosen for the biodegradable and/or bioabsorbable polymer tailored to the specification application for which it will be used.
• the present invention provides processes of making a biodegradable and/or bioabsorbable thermoplastic polyurethane compound tailored for a medical application, as well as the thermoplastic polyurethane compounds themselves.
• bioabsorbable will be used as meaning biodegradable and/or bioabsorbable and/or biosorbable.
• the processes of the invention provide the ability to independently and continuously adjust both the degradation rate and the physical properties based on an understanding of the way that the TPU physical properties and degradation rates interact with each other.
• These relationships include, among others, a relationship between the M n of the polyol in the TPU and amount of phase separation and therefore physical properties, such as rebound.
• properties that affect the degradation rate like hydrophobicity/hydrophilicity balance in the TPU .
• Another such relationship is the relationship between hardness and the hydrophilicity/hydrophobicity balance of the TPU.
• the hydrophobicity/hydrophilicity balance is one of the key properties affecting degradation rate and hardness is one of the key properties affecting the physical and mechanical properties.
• the methods make use of the versatile polyurethane chemistry to prepare polymers with a wide range of physical properties.
• the biodegradation rates of these materials can be varied by adding to the polymeric structure units which can be readily hydrolyzed.
• the number of hydrolysable units in the TPU backbone per unit length is a useful parameter that can be used to control the degradation rate of the exemplary TPU materials. While degradation mechanisms have been studied previously, the ability to independently and continuously vary both the physical properties and the degradation rates has not been demonstrated. Since TPUs have been used in implanted medical devices for many years without and significant safety issues, the exemplary materials combine the excellent toxicological aspects of the component materials used in the polymer synthesis with the opportunity to provide tailorable properties and degradation rates.
• the present invention provides a process of making a bioabsorbable thermoplastic polyurethane compound tailored for a medical application, where the process includes the step of: reacting a polyisocyanate component, a diol chain extender component, and optionally a polyol component, wherein at least one of the components contains hydrolyzable units such that the resulting compound contains hydrolyzable units in its backbone, resulting in a compound with a controllable degradation rate and one or more controllable physical properties, where the degradation rate and the physical properties can be independently set.
• the process of the invention provides a bioabsorbable thermoplastic polyurethane with a desired degradation rate and one or more desired physical properties, where each may be independently selected from a broad range.
• the present invention allows a means of selecting a desired degradation rate for a bioabsorbable thermoplastic polyurethane, in such a way that does not effectively set the physical properties of the bioabsorbable thermoplastic polyurethane, but instead allows one or more physical properties of the bioabsorbable thermoplastic polyurethane to also be selected from a wide range.
• the present invention allows a means of selecting one or more desired physical properties for a bioabsorbable thermoplastic polyurethane, in such a way that does not effectively set the degradation rate of the bioabsorbable thermoplastic polyurethane, but instead allows the degradation rate the bioabsorbable thermoplastic polyurethane to also be selected from a wide range.
• This independent selection of both a degradation rate and one or more desired physical properties of a bioabsorbable thermoplastic polyurethane is the key break through the present invention represents.
• the processes of the invention achieve these results by allowing both the degradation rate and the one or more physical properties of the bioabsorbable thermoplastic polyurethane to be adjusted using different parameters.
• the degradation rate of the compound is set by adjusting one or more degradation rate parameters and the one or more physical properties of the compound is/are set by adjusting one or more physical property parameters, resulting in a bioabsorbable thermoplastic polyurethane compound having at least one desired physical property of the compound, and a desired degradation rate of the compound, independently set.
• the degradation rate parameter may include at least one of the following: (i) the quantity of bioabsorbable units in the backbone of the overall compound; (ii) the molecular weight of the polyol component; (iii) the hydrophilicity of the overall compound; (iv) the molecular weight of the overall compound; (v) the hard segment content of the overall compound; (vi) the crystall inity of the overall compound.
• the physical property may include at least one of the following: (a) the tensile strength of the overall compound; (b) the hardness of the overall compound; (c) the stiffness (flexibility) of the overall compound; (d) the resilience of the overall compound; (e) the abrasion resistance of the overall compound; (f) the water swell of the overall compound; (g) the moisture permeability of the compound; (h) the impact strength/resistance of the compound; (i) the coefficient of friction (on the surface) of the compound; (j) the creep of the compound; (k) the modulus of elasticity of the compound; and (I) the thermal transition points (Tg, Tm) of the compound.
• the physical property parameter may include at least one of the following: (i) the hard segment content of the overall compound; (ii) the molecular weight the overall compound; (iii) the stoichiometry of the overall compound; (iv) the molecular weight of a polyol component; (v) the hydrophilicity of the overall compound; (vi) the difference in polarity between the soft segments and the hard segments of the overall compound; (vii) the difference in the degree of hydrogen bonding between the soft segments and hard segments; (viii) the molecular weight of the soft segment; and (ix) the crystall inity of the overall compound.
• the physical property parameter includes the stoichiometry of the overall compound, which can be adjusted by varying the molar ratio of the polyol derived component to the chain extender derived component; and/or the molar ratio of isocyanate to any active hydrogen groups, for example any hydroxyl groups, in the formulation .
• the physical property may include tensile strength and/or hardness and the physical property parameter includes the molecular weight of the overall compound and/or the hard segment content.
• the physical property may include stiffness and the physical property parameter includes the hard segment content and/or the hydrophilicity of a polyol-derived component of the thermoplastic polyurethane.
• the degradation rate parameter includes the quantity of bioabsorbable units in a backbone structure of the overall compound, wherein bioabsorbable units includes hydrolysable units, enzymatically cleavable units, or combinations thereof.
• the hydrolysable units and enzymatically cleavable units can be derived from the chain extender and/or the polyol.
• the invention provides a process of preparing a bioabsorbable thermoplastic polyurethane compound by adjusting the formulation of a base thermoplastic polyurethane compound in order to generate a bioabsorbable thermoplastic polyurethane compound with the desired combination of properties, and more specifically the desired degradation rate in combination with one or more desired physical properties.
• the base thermoplastic polyurethane is a TPU with the desired physical properties but not the desired degradation rate.
• the base thermoplastic polyurethane is a TPU with the desired degradation rate but not the desired physical properties.
• the base thermoplastic polyurethane is a TPU with close to the desired physical properties but not the desired degradation rate.
• the base thermoplastic polyurethane is a TPU with close to the desired degradation rate but not the desired physical properties. In some embodiments, the base thermoplastic polyurethane is a TPU with close to the desired degradation rate and close to the desired physical properties, in other words a readily available TPU whose properties are as close to the desired properties as possible. The processes of the present invention are then used to adjust the formulation of the TPU so that the end result is a modified TPU with the desired combination of properties.
• the desired degradation rate is higher than that of a base thermoplastic polyurethane compound
• the adjusting of the degradation rate of the thermoplastic polyurethane is accomplished, independent of any adjustment of one or more physical properties of the base thermoplastic polyurethane compound, by at least one of: (a) increasing the number of bioabsorbable units in the backbone structure of the base thermoplastic polyurethane compound per unit length of the backbone; (b) increasing the hydrophilicity of the base thermoplastic polyurethane compound; (c) increasing the molecular weight of the polyol- derived component; (d) decreasing the hard segment content of base thermoplastic polyurethane compound; and (e) decreasing the crystallinity of the base thermoplastic polyurethane compound .
• the use of one or more of these adjustors allows the process to result in a bioabsorbable thermoplastic polyurethane compound with the desired degradation rate.
• the desired degradation rate is lower than that of a base thermoplastic polyurethane compound
• the adjusting of the degradation rate of the thermoplastic polyurethane is accomplished, independent of any adjustment of one or more physical properties of the base thermoplastic polyurethane compound, by at least one of: (a) decreasing the number of bioabsorbable units in the backbone structure of the base thermoplastic polyurethane compound per unit length of the backbone; (b) decreasing the hydrophilicity of the base thermoplastic polyurethane compound; (c) decreasing the molecular weight of the polyol-derived component; (d) increasing the hard segment content of base thermoplastic polyurethane compound; and (e) increasing the crystallinity of the base thermoplastic polyurethane compound .
• the use of one or more of these adjustors allows the process to result in a bioabsorbable thermoplastic polyurethane compound with the desired degradation rate.
• the desired physical property of the thermoplastic polyurethane compound is higher than the physical property of a base thermoplastic polyurethane compound, and wherein the adjusting of the physical property the thermoplastic polyurethane is accomplished, independent of any adjustment of the degradation rate of the thermoplastic polyurethane, by at least one of: (a) increasing the hard segment content of the base thermoplastic polyurethane compound by altering a ratio of a polyol to a chain extender in the formulation; (b) increasing the molecular weight of the base thermoplastic polyurethane compound by varying a stoichiometric ratio of isocyanate to an amount of active hydrogen groups in the thermoplastic polyurethane compound; (c) increasing the crystallinity of the polyol-derived component; and (d) increasing the difference in polarity between hard segment components and soft segment components of the base thermoplastic polyurethane.
• the use of one or more of these adjustors allows the process to result in a bioabsorbable thermoplastic polyurethane
• the desired physical property of the thermoplastic polyurethane compound is lower than the physical property of a base thermoplastic polyurethane compound, and wherein the adjusting of the physical property of the thermoplastic polyurethane is accomplished, independent of any adjustment of the degradation rate of the thermoplastic polyurethane, by at least one of: (a) decreasing the hard segment content of the base thermoplastic polyurethane compound by altering the ratio of a polyol to a chain extender in the formulation; (b) decreasing the molecular weight of the base thermoplastic polyurethane compound by varying a stoichiometric ratio of isocyanate to an amount of active hydrogen groups in the thermoplastic polyurethane compound; (c) decreasing the crystallinity of a polyol-derived component; and (d) decreasing the difference in polarity between hard segment components and soft segment components of the base thermoplastic polyurethane.
• the use of one or more of these adjustors allows the process to result in a bioabsorbable thermoplastic polyurethane compound
• the desired tensile strength of the thermoplastic polyurethane compound is higher than the tensile strength of a base thermoplastic polyurethane compound, and wherein the adjusting of the tensile strength the thermoplastic polyurethane is accomplished, independent of any adjustment of the degradation rate of the thermoplastic polyurethane, by at least one of: (a) increasing the hard segment content of the base thermoplastic polyurethane compound by altering a ratio of a polyol to a chain extender in the formulation; (b) increasing the molecular weight of the base thermoplastic polyurethane compound by varying a stoichiometric ratio of isocyanate to an amount of active hydrogen groups in the thermoplastic polyurethane compound; (c) increasing the crystallinity of the polyol-derived component; and (d) increasing the difference in polarity between hard segment components and soft segment components of the base thermoplastic polyurethane.
• the use of one or more of these adjustors allows the process to result in a
• the desired tensile strength of the thermoplastic polyurethane compound is lower than the tensile strength of a base thermoplastic polyurethane compound, and wherein the adjusting of the tensile strength of the thermoplastic polyurethane is accomplished, independent of any adjustment of the degradation rate of the thermoplastic polyurethane, by at least one of: (a) decreasing the hard segment content of the base thermoplastic polyurethane compound by altering the ratio of a polyol to a chain extender in the formulation; (b) decreasing the molecular weight of the base thermoplastic polyurethane compound by varying a stoichiometric ratio of isocyanate to an amount of active hydrogen groups in the thermoplastic polyurethane compound; (c) decreasing the crystallinity of a polyol-derived component; and (d) decreasing the difference in polarity between hard segment components and soft segment components of the base thermoplastic polyurethane.
• the use of one or more of these adjustors allows the process to result in
• the hardness of the thermoplastic polyurethane compound is higher than the hardness of a base thermoplastic polyurethane compound, and wherein the adjusting of the hardness the thermoplastic polyurethane is accomplished, independent of any adjustment of the degradation rate of the thermoplastic polyurethane, by at least one of: (a) increasing the hard segment content of the base thermoplastic polyurethane compound by altering a ratio of a polyol to a chain extender in the formulation; (b) decreasing the molecular weight of the polyol component used to prepare the base thermoplastic polyurethane compound; and (c) increasing the crystallinity of the polyol-derived component.
• the use of one or more of these adjustors allows the process to result in a bioabsorbable thermoplastic polyurethane compound with the desired hardness.
• the desired hardness of the base thermoplastic polyurethane compound is lower than the hardness of a base thermoplastic polyurethane compound, and wherein the adjusting of the hardness of the thermoplastic polyurethane is accomplished, independent of any adjustment of the degradation rate of the thermoplastic polyurethane, by at least one of: (a) decreasing the hard segment content of the base thermoplastic polyurethane compound by altering a ratio of a polyol to a chain extender in the formulation; (b) increasing the molecular weight of the polyol component used to prepare the base thermoplastic polyurethane compound; and (c) decreasing the crystallinity of the polyol-derived component.
• the use of one or more of these adjustors allows the process to result in a bioabsorbable thermoplastic polyurethane compound with the desired hardness.
• the desired moisture permeability of the thermoplastic polyurethane compound is higher than the moisture permeability of a base thermoplastic polyurethane compound, and wherein the adjusting of the moisture permeability the thermoplastic polyurethane is accomplished, independent of any adjustment of the degradation rate of the thermoplastic polyurethane, by at least one of: (a) decreasing the hard segment content of the base thermoplastic polyurethane compound by altering a ratio of a polyol to a chain extender in the formulation; (b) decreasing the molecular weight of the polyol component used to prepare the base thermoplastic polyurethane compound; (c) increasing the crystallinity of the polyol-derived component; and (d) increasing the hydrophilicity of the polyol component used to prepare the base thermoplastic polyurethane.
• the use of one or more of these adjustors allows the process to result in a bioabsorbable thermoplastic polyurethane compound with the desired moisture permeability.
• the desired moisture permeability of the thermoplastic polyurethane compound is lower than the moisture permeability of a base thermoplastic polyurethane compound, and wherein the adjusting of the moisture permeability of the thermoplastic polyurethane is accomplished, independent of any adjustment of the degradation rate of the thermoplastic polyurethane, by at least one of: (a) increasing the hard segment content of the base thermoplastic polyurethane compound by altering a ratio of a polyol to a chain extender in the formulation; (b) increasing the molecular weight of the polyol component used to prepare the base thermoplastic polyurethane compound; (c) decreasing the crystallinity of the polyol-derived component; and (d) decreasing the hydrophilicity of the polyol component used to prepare the base thermoplastic polyurethane.
• the use of one or more of these adjustors allows the process to result in a bioabsorbable thermoplastic polyurethane compound with the desired moisture permeability.
• the degradation rate is expressed as a function of at least one of: a change in molecular weight with time, a change in tensile strength with time, and a change in weight of the polymer with time.
• the polyisocyanate comprises an aliphatic diisocyanate
• the polyol is selected from the group consisting of polyester polyols, polyether polyols, and combinations and derivatives thereof
• the chain extender is selected from the group consisting of diols, diamines, and combinations thereof.
• the isocyanate is selected from the group consisting of 4,4'-methylene dicyclohexyl diisocyanate (HMDI), 1 ,6-hexane diisocyanate (HDI), 1 ,4-butane diisocyanate (BDI), L-lysine diisocyanate (LDI), 2,4,4-trimethylhexamethylenediisocyanate, and combinations thereof.
• HMDI 4,4'-methylene dicyclohexyl diisocyanate
• HDI 1 ,6-hexane diisocyanate
• BDI 1 ,4-butane diisocyanate
• L-lysine diisocyanate L-lysine diisocyanate
• 2,4,4-trimethylhexamethylenediisocyanate 2,4,4-trimethylhexamethylenediisocyanate
• the polyol is selected from the group consisting of poly lactic acid (PLA), polyglycolic acid (PGA), polybutylene adipate, polybutylene succinate, poly-1 ,3-propylene succinate, polycaprolactone, poly(lactide-co-caprolactone), copolymers of two or more thereof, and mixtures thereof.
• the chain extender is selected from the group consisting of 1 ,4-butanediol, 2-ethyl-1 ,3-hexanediol (EHD), 2,2,4- trimethyl pentane-1 ,3-diol (TMPD), 1 ,6-hexanediol, 1 ,4-cyclohexane dimethanol, 1 ,3-propanediol, diethylene glycol, dipropylene glycol, and combinations thereof.
• EHD 2-ethyl-1 ,3-hexanediol
• TMPD 2,2,4- trimethyl pentane-1 ,3-diol
• 1 ,6-hexanediol 1 ,4-cyclohexane dimethanol
• 1 ,3-propanediol diethylene glycol, dipropylene glycol, and combinations thereof.
• the bioabsorbable unit of the polyol may be derived from lactic acid, glycolic acid, caprolactone, or a combination thereof.
• the present invention also provides for a bioabsorbable thermoplastic polyurethane compound, tailored for a medical application, where the compound comprises the reaction product of a polyisocyanate component, a diol chain extender component, and optionally a polyol component, wherein at least one of the components contains hydrolyzable units such that the resulting compound contains hydrolyzable units in its backbone.
• the degradation rate of the compound is set by adjusting one or more degradation rate parameters and at least one physical property of the compound is set by adjusting one or more physical property parameters.
• the bioabsorbable thermoplastic polyurethane compound thus has at least one physical property and a degradation rate which are independently set.
• the bioabsorbable thermoplastic polyurethane compound of the invention may be a bioabsorbable thermoplastic polyurethane compound with a degradation rate higher than that of a base thermoplastic polyurethane compound on which the bioabsorbable thermoplastic polyurethane compound is based .
• the degradation rate of the base thermoplastic polyurethane compound can be adjusted to the higher rate of the bioabsorbable thermoplastic polyurethane compound, independent of any adjustment of one or more physical properties of the base thermoplastic polyurethane compound, by at least one of: (a) increasing the number of bioabsorbable units in the backbone structure of the base thermoplastic polyurethane compound per unit length of the backbone; (b) increasing the hydrophilicity of the base thermoplastic polyurethane compound; (c) increasing the molecular weight of the polyol-derived component; (d) decreasing the hard segment content of base thermoplastic polyurethane compound; and (e) decreasing the crystallinity of the base thermoplastic polyurethane compound .
• the bioabsorbable thermoplastic polyurethane compound of the invention may be a bioabsorbable thermoplastic polyurethane compound with a degradation rate lower than that of a base thermoplastic polyurethane compound on which the bioabsorbable thermoplastic polyurethane compound is based.
• the degradation rate of the base thermoplastic polyurethane compound can be adjusted to the lower rate of the bioabsorbable thermoplastic polyurethane compound, independent of any adjustment of one or more physical properties of the base thermoplastic polyurethane compound, by at least one of: (a) decreasing the number of bioabsorbable units in the backbone structure of the base thermoplastic polyurethane compound per unit length of the backbone; (b) decreasing the hydrophilicity of the base thermoplastic polyurethane compound; (c) decreasing the molecular weight of the polyol-derived component; (d) increasing the hard segment content of base thermoplastic polyurethane compound; and (e) increasing the crystallinity of the base thermoplastic polyurethane compound .
• the bioabsorbable thermoplastic polyurethane compound of the invention may be a bioabsorbable thermoplastic polyurethane compound with one or more physical properties, for example tensile strength, higher than those of a base thermoplastic polyurethane compound on which the bioabsorbable thermoplastic polyurethane compound is based.
• the physical property such as the tensile strength of the base thermoplastic polyurethane compound
• the bioabsorbable thermoplastic polyurethane compound of the invention may be a bioabsorbable thermoplastic polyurethane compound with one or more physical properties, for example, tensile strength, lower than those of a base thermoplastic polyurethane compound on which the bioabsorbable thermoplastic polyurethane compound is based.
• the physical property such as the tensile strength of the base thermoplastic polyurethane compound
• the bioabsorbable thermoplastic polyurethane compound is prepared from an aliphatic diisocyanate; a polyol selected from the group consisting of polyester polyols, polyether polyols, and combinations and derivatives thereof; a chain extender selected from the group consisting of diols, diamines, and combinations thereof.
• the bioabsorbable thermoplastic polyurethane compound is prepared from a isocyanate selected from the group consisting of 4,4'-methylene dicyclohexyl diisocyanate (HMDI), 1 ,6- hexane diisocyanate (HDI), 1 ,4-butane diisocyanate (BDI), L-lysine diisocyanate (LDI), 2,4,4-trimethylhexannethylene diisocyanate, and combinations thereof; a polyol selected from the group consisting of poly lactic acid (PLA), polyglycolic acid (PGA), polybutylene adipate, polybutylene succinate, poly-1 ,3-propylene succinate, polycaprolactone, poly(lactide-co-caprolactone), copolymers of two or more thereof, and mixtures thereof; and a chain extender is selected from the group consisting of 1 ,4-butanediol, 2-ethyl
• HMDI 4,4'
• the bioabsorbable thermoplastic polyurethane compound contains bioabsorbable units derived from lactic acid, glycolic acid, caprolactone, or a combination thereof, where such units may have been present in the polyol and/or the chain extender used to prepare the bioabsorbable thermoplastic polyurethane compound.
• each of the variables identified for adjusting the degradation rate and the physical properties of a TPU are very often interrelated with one another and can have an impact on physical properties and degradation rates. That is, changing any one of these identified variables may impact the physical properties and degradation rates of a TPU, but the process of the invention, through coordinated adjustment of two or more of these variables allow for the physical properties and degradation rates of the TPU to be independently set.
• aspects of the invention relate to a process for the preparation of bioabsorbable polymers which may be prepared to have physical properties and degradation rates chosen and independently set.
• the invention allows both the physical and mechanical properties and the biodegradation rates of polymers to be independently modified to precisely match the needs of the application or to fit a particular patient profile.
• the described bioabsorbable polymers through minor variations of ratios and/or specific identifies of ingredients used, allow significant differences in bioabsorption rate and physical properties to be achieved independently of one another.
• a bioabsorbable polymer is a polymer which when placed into the body of a human or animal subject is degraded and/or absorbed by the body, for example, by hydrolyzation and/or enzymatic cleavage.
• the bioabsorption properties of the polymer are simulated through measurable biodegradation properties.
• a bioabsorbable polymer thus has one or more biodegradation properties, such as a change in molecular weight with time, a change in tensile strength with time, a change in weight of the polymer with time, or a combination thereof when placed in the body.
• the biodegradation property can be estimated, for example, through in vitro measurements in conditions which simulate the conditions to which the bioabsorbable polymer is expected to be exposed in the body.
• the measured change in the biodegradation property, under such test conditions is generally no less than 10% over the course of a year.
• a wide variation in the biodegradation properties of the exemplary polymers is provided in order to enable candidate polymers to be identified which cover a range of the biodegradation property.
• the bioabsorbable polymers of the invention include bioabsorbable thermoplastic polyurethane compounds.
• a thermoplastic polyurethane is a polyurethane which includes hard segments and soft segments. The hard segments are generally derived from an isocyanate and a chain extender. The soft segments are derived from a polyol.
• polyurethane as used herein includes polyureas and compounds with both urethane and urea linkages.
• the soft segment provides some or all of the biodegradation properties of the polymer, although in some embodiments, at least some of the degradation properties are influenced and/or provide by the chain extender.
• thermoplastic polyurethane compound (TPU) can thus be a multi-block copolymer which is the reaction product of a) at least one polyol, b) at least one chain extender, c) at least one isocyanate, and d) optionally at least one catalyst, and e) optionally at least one additive, other than the components a), b), c) and d).
• Component (a) provides the soft segment of the final TPU material.
• Suitable polyols include OH-terminated oligomeric glycols, such as polyether polyols, polyester polyols, and mixtures and derivatives thereof.
• Exemplary polyether polyols include polyethylene glycol (PEG), and poly(trimethylene oxide) glycol (PTMEG).
• polyester polyols include aliphatic polyester polyols, such as copolymers of a cyclic lactone (such as lactide, glycolide, acetolactone, beta-propiolactone, caprolactone, valerolactone, butyrolactone, pivalolactone, or decalactone) and an a- hydroxy acid or ester thereof (such as lactic acid or glycolic acid), and polymer blends thereof.
• polyester polyols include poly(lactide-co-caprolactone), and poly(glycolide-co-caprolactone).
• polyester polyols include polylactic acid, polyalkylene adipates (such as poly(butylene adipate), poly(ethylene adipate), poly(hexamethylene adipate), poly(tetramethylene-co-hexannethylene adipate)), succinates (such as poly(butylene succinate), poly-(1 ,3-propylene succinate)), polycarbonate polyols (such a poly(hexamethylene carbonate), poly(pentamethylene carbonate), poly(trimethylene carbonate)), copolymers of two or more thereof, and mixtures thereof.
• polyalkylene adipates such as poly(butylene adipate), poly(ethylene adipate), poly(hexamethylene adipate), poly(tetramethylene-co-hexannethylene adipate)
• succinates such as poly(butylene succinate), poly-(1 ,3-propylene succinate)
• polycarbonate polyols such
• Component (a) can also be the condensation product of a short (e.g., MW (400 - 1000Mn)) polyester glycol and an a- hydroxy acid, such as lactic acid, glycolic acid, or a mixture thereof.
• Component (a) can also be the condensation product of an a-hydroxy acid, an alkylene diacid (such as one or more of adipic acid, succinic acid, sebacic acid, azelaic acid), and an alkylene diol (such as one or more of ethylene glycol, propylene glycol, butanediol, hexanediol).
• Component (a) can also be an alpha, omega-hydroxy telechelic random copolymer of at least one of a cyclic lactone, a carbonate, and an ester monomer, such as D-lactide, L-lactide, meso-lactide, glycolide, dioxanone, trimethyl carbonate, acetolactone, propiolactone, butyrolactone, valerolactone, and caprolactone.
• One particularly suitable polyol includes poly(lactide-co-caprolactone) or a derivative thereof.
• the polyol component may also include a diamine, including any of the diamines described herein, as well as any similarly active-hydrogen compounds that are reactive with isocyanate groups.
• a diamine including any of the diamines described herein, as well as any similarly active-hydrogen compounds that are reactive with isocyanate groups.
• the hydroxyl groups of the polyols described above being one of the most suitable examples.
• the mole ratio of cyclic lactone (e.g., caprolactone) to a-hydroxy acid (e.g., lactic acid) in the copolymer can be about 95:5 to about 30:70, such as from 45:55 to 30:70 or from about 95:5 to about 5:95.
• polyester/polyether polyols can be random, block, segmented, tapered blocks, graft, tri-block, etc., having a linear, branched, or star structure.
• the weight average molecular weight of component (a) (polyol) within the exemplary polymer can be up to 20,000, and in one embodiment, up to 10,000, such as in the range of 500 - 5000.
• a glass transition temperature of component a) can be lower than ambient temperature (e.g., lower than 25°C) and in one embodiment, lower than 0°, or lower than - 15°C.
• component (a) can be chosen so that it is sufficiently different in polarity, has the ability to hydrogen-bond, and other such properties known to those skilled in the art so that it will effectively phase separate from the hard segment of the multi-block copolymer that is formed on reaction of the various components. Lack of phase separation can result in the properties of the final product being compromised, although for some applications, such lack of phase separation may be acceptable or even useful .
• Component (b) is generally a low molecular weight diol or diamine chain extender.
• Suitable chain extenders include diols, diamines, and combinations thereof.
• Exemplary chain extenders include alkane diols of from 1 -30 carbon atoms, ethylene glycol, 1 ,3-propanediol, 1 ,2-propanediol, 1 ,4-butanediol, pentanediol, hexamethylenediol, heptanediol, nonanediol, dodecanediol, 2-ethyl-1 ,3-hexanediol (EHD), 2,2,4-trimethyl pentane-1 ,3-diol (TMPD), 1 ,6-hexanediol, 1 ,4-cyclohexane dimethanol, diethylene glycol, dipropylene glycol, and combinations thereof.
• Suitable diamine chain extenders can be aliphatic or aromatic in nature, such as alkylenediamines of from 1 -30 carbon atoms (e.g., ethylenediamine, butanediamine, hexamethylenediamine).
• Component (b) can also be synthesized by condensation of an alpha-hydroxy acid, such as lactic acid, glycolic acid, or a mixture thereof, with a small alkylenediol and/or hydroxyl amine molecule of from 1 -20 carbon atoms, such as ethylene glycol, butanediol, hexamethylenediol, ethanolamine, aminobutanol, or a mixture thereof.
• Component (b) can also be synthesized by condensation of an alpha-amino acid such as glycine, lycine or similar amino acids with a small alkylene diol molecule of from 1 -20 carbon atoms such as ethylene glycol, butane diol, hexamethylene diol or a mixture of thereof.
• the chain extender can have a number-average molecular weight Mn of up to 2000 and in some embodiments, up to 1000, such as for example, 100 to 700.
• Component (c) can be a diisocyanate.
• Suitable isocyanates include aliphatic diisocyanates, such as 4,4'-methylene dicylcohexyl diisocyanate (HMDI), 1 ,6-hexane diisocyanate (HDI), 1 ,4-butane diisocyanate (BDI), L-lysine diisocyanate (LDI), 2,4,4- trimethylhexamethylenediisocyanate, other similar diisocyanate, and mixtures thereof.
• HMDI 4,4'-methylene dicylcohexyl diisocyanate
• HDI 1 ,6-hexane diisocyanate
• BDI 1 ,4-butane diisocyanate
• L-lysine diisocyanate L-lysine diisocyanate
• 2,4,4- trimethylhexamethylenediisocyanate other similar diisocyanate, and mixtures thereof.
• diisocyanates which can be used include aromatic diisocyanates such as toluene diisocyanate (TDI), 2,4'-methylene diphenyl diisocyanate, and 4,4'-methylene diphenyl diisocyanate, and mixtures thereof.
• aromatic diisocyanates such as toluene diisocyanate (TDI), 2,4'-methylene diphenyl diisocyanate, and 4,4'-methylene diphenyl diisocyanate, and mixtures thereof.
• Component (c) can be used in an approximately stoichiometrically equivalent amount to the total amount of hydroxyls and amine groups (where present) in the formulation (i.e., in components a) and b)) such that the number of moles of isocyanate groups is equal to the number of moles of hydroxyl and amine groups.
• This favors high MW TPUs with material properties suited to many biomedical applications.
• the molecular weight of the TPU can be controlled to within a desired range.
• a molar ratio of isocyanate groups to hydroxyl plus amine groups is in a range of 0.8-1 .2.
• a monofunctional alcohol, amine, or isocyanate molecule can be utilized in combination with the diisocyanate for controlling the final TPU MW.
• Component (d) can be any suitable urethane polymerization catalyst.
• Some specific examples include metal alkyls, chlorides, esters, and carboxylates, and mixture thereof.
• Amines such as tri(m)ethylamine, triethylenediamine, N-(m)ethylmorpholine, dimethylcyclohexylamine, ⁇ , ⁇ '- dimethylpiperazine, dimethylaniline, ⁇ , ⁇ , ⁇ ' ⁇ '-tetramethylethylenediamine, 1 ,8-diazobicylo[5,4,0]undec-7-ene, and tri(dimethylaminomethyl)phenol, can also be used as catalysts. In some cases, a catalyst is not needed.
• a weight ratio of catalyst (d) to components (a)+(b)+(c) can be from 0:1 to 0.1 :1 , e.g., at least 0.0001 :1 .
• Component (e) is also an optional ingredient and can include one or more performance additives such as process aids, antioxidants, UV- stabilizers, light stabilizers, lubricants, mineral and/or inert fillers, colorants, opacifying pigments, and mixtures thereof.
• a weight ratio of component (e) to components (a)+(b)+(c)+(d) can be from 0:1 to 10:1 , e.g., 0.001 :1 to 1 :1 .
• the hard segment content (%HS) of the copolymer (i.e., the combined content of the components derived from the chain extender and isocyanate, expressed by weight percentage) can range from 2-100 wt. %, 2-95 wt%, and in one embodiment, is at least 5 wt. % or at least 10 wt. %, for at least one of the polymers forming the set of the bioabsorbable polymers.
• the set of polymers includes at least one polymer in each of two or more, or at least three, or at least four non- overlapping ranges, such as selected from the following ranges:
• the soft segment content (%SS) of the copolymer (i.e., the percentage by weight of the components derived from the polyol) can range from 5-95%, and in one embodiment, is at least 25% or at least 40%, for at least one of the polymers forming the set of the bioabsorbable polymers.
• the set of polymers includes at least one polymer in each of two or more, or at least three, or at least four non-overlapping ranges, such as selected from the following ranges:
• the soft segment content can be determined by subtracting the hard segment content from 100%.
• the bioabsorbable polymers include at least one bioabsorbable unit.
• a bioabsorbable unit is one which undergoes hydrolysis and/or enzymatic cleavage under conditions similar to those which the polymer is expected to be exposed in the body.
• the polyol includes at least one bioabsorbable unit.
• the bioabsorbable unit is derived from an a-hydroxy acid, such as poly lactic acid (PLA) in the soft segment.
• PVA poly lactic acid
• at least some of the bioabsorbable units are in the hard segment, e.g., derived from the chain extender.
• the bioabsorbable unit content (e.g., ⁇ -hydroxy acid content) of the soft segment of the copolymer, expressed as a percentage by weight % (% PLA) can range from 2-70 wt. %.
• the set of polymers includes at least one polymer in each of two or more, or at least three, or at least four non-overlapping ranges, such as selected from the following ranges:
• the exemplary polymers are useful for a wide variety of biomedical applications.
• the polymers can be readily tailored to provide selected biodegradation properties and physical and mechanical properties that are suited for a specific application/patient.
• the physical property described above can be selected from a finite set of physical properties.
• the selectable physical properties may include one or more of the following: tensile strength, hardness, stiffness (flexibility), resilience, abrasion resistance, impact resistance, coefficient of friction (on the surface of the TPU), creep, modulus of elasticity, thermal transition points (T g , T m ), water absorption, moisture permeability, contact angle, electrostatic properties such as surface and volume resistivity and conductivity, and combinations thereof.
• Methods for determining some of these properties and the units in which they can be expressed are given by way of example.
• Tensile strength This can be determined according to ASTM D638 - 10 Standard Test Method for Tensile Properties of Plastics. Exemplary polymers have initial tensile strengths, according to this test method, in the range of 5 - 80 MPa, such as 35-70MPa. Percentage change in tensile strength can be used as a degradation property, as noted below.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their tensile strength by at least 5 MPa, or at least 10 MPa, or at least 20 MPa, or vary by at least 10%, or at least 20%, or at least 30%.
• Hardness This can be determined according to ASTM D2240- 05(2010) Standard Test Method for Rubber Property— Durometer Hardness, DOI: 10.1520/D2240-05R10.
• Exemplary polymers have a hardness, according to this test method in the range of 60 Shore A - 85 Shore D, e.g., 65-95 Shore A or even 65-75 Shore A.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their hardness by at least 5 Shore A, or at least 10 Shore A, or at least 20 Shore A, or vary by at least 10%, or at least 20%.
• Stiffness This can be determined according to ASTM D790-10 Standard Test Methods for Flexural Properties of Unreinforced and Reinforced Plastics and Electrical Insulating Materials, DOI: 10.1520/D0790- 10.
• Exemplary polymers have a stiffness, according to this test method, in the range of 5-15000 MPa.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their stiffness by at least 5 MPa, or at least 20 MPa, or at least 1000 MPa, or vary by at least 10%, or at least 20%, or at least 30%.
• Resilience (rebound) This can be determined according to ASTM D2632-01 (2008) Standard Test Method for Rubber Property— Resilience by Vertical Rebound, DOI: 10.1520/D2632-01 R08.
• Exemplary polymers have a resilience, according to this test method, in the range of 1 -95%, such as 30- 80%.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their resilience by at least 5%, or at least 10%, or at least 20%.
• Abrasion resistance This can be deternnined according to ASTM D3389-10 Standard Test Method for Coated Fabrics Abrasion Resistance (Rotary Platform Abrader); DOI: 10.1520/D3389-10 (Taber, H 18 wheel, 1000g).
• Exemplary polymers have an abrasion resistance, according to this test method, in the range of 2 - 400 mg/1000 cycles, such as 2 - 100 mg/1000 cycles.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their abrasion resistance by at least 5 mg, or at least 10 mg, or at least 20 mg, or vary by at least 10%, or at least 20%, or at least 30%.
• Impact Resistance This can be determined according to ASTM D256-10 Standard Test Methods for Determining the Izod Pendulum Impact Resistance of Plastics; DOI: 10.1520/D0256-10.
• Exemplary polymers have an impact resistance, according to this test method, in the range of No failure - 10 ft-lb/in, such as No failure - 2 ft-lb/in. Percentage change in impact resistance can be used as a degradation property, as noted below.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their impact resistance by at least 1 ft-lb/in or at least 2 ft-lb/in, or vary by at least 10%, or at least 20%.
• Coefficient of friction (on the surface of the TPU): This can be determined according to ASTM D1894-1 1 e1 Standard Test Method for Static and Kinetic Coefficients of Friction of Plastic Film and Sheeting, DOI: 10.1520/D1894-1 1 E01 .
• Exemplary polymers have a coefficient of friction, according to this test method, in the range of 0.5 - 10.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their coefficient of friction by at least 0.5, or at least 1 .0, or vary by at least 5%, or at least 10%, or at least 20%.
• Creep This can be determined according to ASTM D2990-09 Standard Test Methods for Tensile, Compressive, and Flexural Creep and Creep-Rupture of Plastics, DOI: 10.1520/D2990-09. Exemplary polymers have creep, according to this test method, in the range of 5-95%, or 50-40%.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their creep by at least 5%, or at least 1 0%, or at least 20%.
• Modulus of elasticity This can be determined according to ASTM F1635-1 1 .
• Exemplary polymers have a modulus of elasticity, according to this test method, in the range of 10 - 2000 MPa.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their modulus of elasticity by at least 10 MPa, or at least 20 MPa, or at least 100 MPa, or vary by at least 5%, or at least 10%, or at least 20%.
• Thermal transition points (gas transition temperature, T g , melting point T m ): These can be determined according to ASTM D3418 - 08 Standard Test Method for Transition Temperatures and Enthalpies of Fusion and Crystallization of Polymers by Differential Scanning Calorimetry; DOI: 10.1520/D3418-08.
• Exemplary polymers have a T g , according to this test method, in the range of -60 - 50°C, e.g., -60 -0°C, and a T m of 80 - 200°C.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their T g or T m by at least 10°C, or at least 20°C, or at least 100°C.
• Water absorption This can be determined according to ASTM D570 - 98(2010)e1 Standard Test Method for Water Absorption of Plastics; DOI : 10.1520/D0570-98R10E01 .
• Exemplary polymers have a water absorption, according to this test method, in the range of 0.5 - 1000%, e.g., 5 - 600%.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their water absorption by at least 10%, or at least 50%, or at least 100%.
• Water Vapor Transmission (Moisture permeability): This can be determined according to ASTM E96/E96M-10 Standard Test Methods for Water Vapor Transmission of Materials, DOI : 10.1520/E0096_E0096M-10 (Upright cup, 23°C, 50%RH).
• Exemplary polymers have a moisture permeability, according to this test method, in the range of 0 - 900 g/m 2* 24h.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their moisture permeability by at least 10 g/m 2* 24h, or at least 100 g/m 2* 24h, or at least 500 g/m 2* 24h .
• the first parameter can be selected from a predefined set of first parameters. These can include one or more of hard segment content of the thermoplastic polyurethane, molecular weight of the thermoplastic polyurethane, stoichiometry of the thermoplastic polyurethane; a molecular weight of a polyol-derived component of the thermoplastic polyurethane, a hydrophilicity of the overall component and/or the hydrophilicity of a polyol- derived component of the thermoplastic polyurethane, a difference in polarity between the soft segments and the hard segments, a difference in the degree of hydrogen bonding between the soft segments and hard segments, a molecular weight of the soft segment, a polarity of the soft segments, a crystall inity of the overall compound and/or the crystallinity of the soft segments, and combinations thereof.
• thermoplastic polyurethane %HS, as described above. This can be adjusted by changing a ratio of polyol to chain extender.
• thermoplastic polyurethane this can be the weight average molecular weight M w or the number average molecular weight M n .
• thermoplastic polyurethane Stoichiometry of the thermoplastic polyurethane. This can be described in terms of a molar ratio of the polyol derived component to the chain extender derived component in the formulation and/or by a molar ratio of isocyanate to hydroxyl groups in the formulation.
• Molecular weight of a polyol-derived component of the thermoplastic polyurethane this value may be determined by GPC, according to ASTM F1635-1 1 , or by hydroxyl number determination.
• Exemplary polymers may have a molecular weight of 80-250 KDa, e.g., 100- 200 KDa.
• a hydrophilicity of the overall compound and/or the hydrophilicity of a polyol-derived component of the thermoplastic polyurethane This can be estimated by measuring the contact angle of water with the polymer surface or by water swell .
• the first parameter when the physical property includes tensile strength, can include molecular weight of the thermoplastic polyurethane and optionally also hard segment content. As another example, when the physical property includes hardness, the first parameter can include hard segment content. As another example, when the physical property includes stiffness, the first parameter can include the hard segment content %HS and the optionally hydrophilicity of the polyol-derived component of the thermoplastic polyurethane.
• the degradation rates of the exemplary TPUs depend on a number of factors, which may be referred to as the degradation rate parameter.
• First is the number of hydrolysable units in the TPU's backbone.
• the hydrophilicity of the TPU is also a significant contributor to the degradation rate.
• For a polymer to hydrolyze it must come into contact with water and if a polymer is very hydrophobic, the rate of degradation will be significantly lower for a given percentage of hydrolysable polymer backbone units when compared with a polymer that is more hydrophilic. This tends to be related to the HS% since the HS is significantly more hydrophobic than the soft segment and also sometimes is crystalline which makes permeation of water into the TPU less facile.
• Another factor that impacts the degradation rate is the degree of crystall inity of the polymer. Since the exemplary materials are primarily for use in the body are based on aliphatic isocyanates and this type of TPU does not have crystalline hard segments like aromatic TPUs, the main contributor to crystallinity is the soft segment crystallinity. As the lactic acid content increases, the concentration of hydrolytically labile ester groups increases. Formulations based on amorphous poly(lactide-co-caprolactone) polyols with higher number of ester linkages for a given hard segment content therefore are expected to degrade faster. Lower lactic acid content based formulations are expected to degrade slower due to crystalline (more hydrophobic) nature and lower number of ester linkages.
• Phase mixing which is related to a number of factors including polyol molecular weight and overall TPU Mw, can also affect the rate of degradation. As the more hydrophobic hard phases are more phase-mixed into the hydrolysable soft segments, the overall hydrophobicity of the soft phase will increase and the degradation rate will, as a result, decrease.
• the degradation rate parameter can include one or more of a finite set of parameters, such as one or more of a parameter based on a quantity of bioabsorbable units in a backbone structure of the thermoplastic polyurethane compound, the hydrophilicity of the overall compound and/or the hydrophilicity of the polyol- derived component of the thermoplastic polyurethane compound, a molecular weight of the polyol-derived component, and combinations thereof.
• a finite set of parameters such as one or more of a parameter based on a quantity of bioabsorbable units in a backbone structure of the thermoplastic polyurethane compound, the hydrophilicity of the overall compound and/or the hydrophilicity of the polyol- derived component of the thermoplastic polyurethane compound, a molecular weight of the polyol-derived component, and combinations thereof.
• the parameter based on a quantity (e.g., number average, molar ratio, or the like) of bioabsorbable units in a backbone structure of the thermoplastic polyurethane compound can include one or both of a quantity of hydrolysable units and a quantity of enzymatically cleavable units.
• This can be the %PLA in the polyol which may also contain other units which are less liable to hydrolyze, as described above, i.e., the bioabsorbable units in the soft segment.
• other components that contribute segments to the backbone of the bioabsorbable polymer, including the chain extender may also include bioabsorbable units and these may be included in the overall quantity of bioabsorbable units.
• the invention includes the proviso that the one or more degradation rate parameters used is in the process are each different from the one or more physical property parameters used in the process and in some cases more than one parameter must be adjusted to maintain the degradation rate while adjusting one or more physical properties to the desired level, while in other cases more than one parameter must be adjusted to maintain one or more physical properties, while adjusting the degradation rate to the desired level.
• the degradation property (which may be referred to as the degradation rate) can be expressed as a function of at least one of: a change in molecular weight of the polymer with time, a change in tensile strength of the polymer with time, a change in impact resistance of the polymer with time, and a change in weight of the polymer with time.
• These values can be determined in vitro, in a suitable test environment, such as a liquid, with properties of the TPU being measured at intervals, such as days, weeks, or months. In the exemplary embodiment, these degradation properties are measured according to ASTM 1635-1 1 .
• the change in tensile strength can be expressed as a percentage of the initial value, where the initial and subsequent values are measured according to ASTM 1635-1 1 , as described above.
• the present invention may allow a base thermoplastic polyurethane to be modified such that its initial tensile strength is adjusted by at least 20%, or at least 40%, or at least 60% upward, and in other embodiments by at least 20%, or at least 40%, or at least 60% downward.
• the adjustment may be to the tensile strength as measured 8 weeks after being inserted into the environment where the material is expected/desired to degrade (i.e., a patient's body), where the same adjustments are possible.
• Weight loss The change in weight can be measured according to ASTM 1635-1 1 , expressed as a percentage of the initial value.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their % change in weight over eight weeks by at least 20%, or at least 40%, or at least 60%.
• Molecular Weight loss The change in molecular weight can be measured according to ASTM 1635-1 1 , expressed as in KDa.
• the set of polymers contemplated by the invention may include polymers which are adjusted in their % change in molecular weight over eight weeks by at least 20%, or at least 40%, or at least 60%.
• the degradation property is measured according to ASTM F1635-1 1 (Standard test method for in vitro degradation testing of hydrolytically degradable polymer resins and fabricated forms for surgical implants).
• ASTM F1635-1 1 Standard test method for in vitro degradation testing of hydrolytically degradable polymer resins and fabricated forms for surgical implants.
• This test method is specified for use with polymers that are known to degrade primarily by hydrolysis, such as homopolymers and copolymers of /-lactide, cZ-lactide, c/,/-lactide glycolide, caprolactone, and p- dioxanone.
• PBS phosphate buffered saline
• the degradation property can be computed, based on these measurements, and can be expressed as, for example, a loss in the property over a specified time interval, either from the start of the immersion, or starting at a specified time thereafter.
• the degradation property can be expressed in other ways, such as, for example, the time to reach a specified loss in the property such as a specified weight loss or specified percentage change in weight (e.g., a 50% weight loss), or the like.
• the properties of the exemplary TPU's tend to be highly dependent on the polymer's molecular weight (Mw), hard segment content (HS%), polyol chemical identity and the degree of phase separation (PS) of the TPU.
• Mw molecular weight
• HS% hard segment content
• PS polyol chemical identity
• the design of the polymer typically takes place by adjusting the factors (HS%, Mw, PS, polyol chemical identity, etc.) to achieve a TPU which is expected to have the approximate properties required.
• the ratio of polyol to chain extender can be adjusted. This would be a primary factor controlling the stiffness (flex modulus) of the polymer.
• the Mw of the polymer can be controlled by varying the stoichiometry (ratio of isocyanate to hydroxyl groups) or by the addition of a monofunctional hydroxyl containing component. This is a significant factor that controls the tensile strength of the polymer although hardness (HS%), phase separation and various other parameters have an effect on this as well but their effect is of a lesser extent. There are other parameters that impact the properties, which include the chemical identity and molecular weight of the polyol used to for the TPU.
• the chemical identity determines the hydrophilicity/hydrophobicity balance of the TPU formed (which affects water absorption and moisture permeability of the material) and some of the thermal properties of the polymer along with various other properties such as toughness and abrasion resistance.
• the balancing of each of these requirements for a given application can often only be an approximation, is there are numerous tradeoffs as one property is maximized others are lowered (see Table 1 below).
• the design of a bioresorbable TPU with a specified degradation rate and set of physical properties can thus involve an iterative process whereby the major controllable parameters which affect the physical properties, such as HS%, Mw, polyol molecular weight and chemical identity, stoichiometry, etc., are selected along with the parameters which affect the degradation rate such as number of hydrolysable units in the backbone and the hydrophilicity of the polyol and the polyol molecular weight are chosen.
• the major controllable parameters which affect the physical properties such as HS%, Mw, polyol molecular weight and chemical identity, stoichiometry, etc.
• Some parameters may affect both the degradation rate and one or more physical properties of the bioresorbable TPU, and so in some embodiments a second, or even a third parameter is also adjusted along with the first, in order to arrive at a TPU with the desired combination of properties, that is the desired degradation rate and one or more physical properties.
• This initial set of parameters is used to prepare a base TPU which and the properties and degradation rate of this material are measured. Based on the results of these initial measurements, a number of additional TPUs are produced, by varying the parameters in such a way that is designed to produce a material that more closely matches the requirements of the application . For example, to produce a material that has the same physical properties as the initial TPU but with a faster degradation rate, then the next set of materials could be prepared using a polyol that has a higher number of hydrolysable units in its backbone or which has a higher hydrophilic character compared to the first polymer.
• the adjustment by the modification component can include at least one of: (a) increasing (or decreasing) a number of bioabsorbable units in a backbone structure of the base thermoplastic polyurethane compound per unit length of the backbone; (b) increasing (or decreasing) a hydrophilicity of a polyol-derived component of the thermoplastic polyurethane compound; (c) increasing (or decreasing) a molecular weight of the polyol-derived component; (d) decreasing (or increasing) a molecular weight of the thermoplastic polyurethane compound; (e) decreasing (or increasing) a hard segment content of the thermoplastic polyurethane compound; and (f) decreasing (or increasing) a crystallinity of the thermoplastic polyurethane compound.
• the computing of the at least one thermoplastic polyurethane compound includes at least one of: (a) increasing (or decreasing) a hard segment content of the base thermoplastic polyurethane compound by altering a ratio of a polyol to a chain extender in the formulation; (b) increasing (or decreasing) a molecular weight of the base thermoplastic polyurethane compound by varying a stoichiometric ratio of isocyanate to an amount of hydroxyl groups in the thermoplastic polyurethane compound; (c) increasing (or decreasing) the crystallinity of a polyol-derived component; and (d) increasing (or decreasing) a difference in polarity between hard segment components (isocyanate and chain extender) and soft segment components (polyol) of the polymer.
• TPU 1 has tensile strength of X, hardness of Y, and biodegradation rate of Z. If the customer seeks TPU 2 with the following:
• the process may include: (1 ) Increasing the hard segment of TPU to increase the hardness; and/or (2) Decreasing the MW of the soft segment to compensate the tensile strength increase with increasing the hard segment; (3) Increasing the hydrolysable units in the soft segment to increase the degradation rate; or (4) Increasing the hard segment content and incorporating hydrolysable units in the hard segment and change the soft segment MW to keep the tensile strength the same.
• the exemplary bioabsorbable copolymers are solids at room temperature and may be liquefied by heating prior to blending with the hard segment components.
• the polyol may be analyzed for hydroxyl number, acid number, and moisture content, and this information can be used to allow a user to adjust the stoichiometry of the components used to prepare the TPU, for example, to obtain a TPU with a higher MW, thus adjusting one or more physical properties and/or the degradation rate of the TPU in the desired direction.
• a blend can be prepared by premixing the polyol(s) and chain extender(s) or by adding these directly to a reaction vessel. This blend can be heated to a suitable reaction temperature prior to combining with the isocyanate, with stirring, followed by addition of catalyst, if any. The temperature of the reaction can be monitored. Prior to setting or gelling, the polymer can be placed in a suitably shaped mold and cured for a suitable time at a curing temperature of, for example, 100-200°C.
• Poly(lactide-co-caprolactone) polyols can be made by ring opening copolymerization of lactide and caprolactone monomers. This results in a random distribution of lactide-derived units and caprolactone-derived units in the polyol, which can be verified by NMR.
• the exemplary method provides the ability to independently and continuously adjust both the degradation rate and the physical properties based on an understanding of the way that the TPU physical properties and degradation rates interact with each other.
• These relationships include, among others, a relationship between the M n of the polyol in the TPU and amount of phase separation and therefore physical properties, such as rebound.
• properties that affect the degradation rate like hydrophobicity/hydrophilicity balance in the TPU.
• Another such relationship is the relationship between hardness and the hydrophilicity/hydrophobicity balance of the TPU .
• the hydrophobicity/hydrophilicity balance is one of the key properties affecting degradation rate and hardness is one of the key properties affecting the physical and mechanical properties.
• the method makes use of the versatile polyurethane chemistry to prepare polymers with a wide range of physical properties.
• the biodegradation rates of these materials can be varied by adding to the polymeric structure units which can be readily hydrolyzed.
• the number of hydrolysable units in the TPU backbone per unit length is a useful parameter that can be used to control the degradation rate of the exemplary TPU materials. While degradation mechanisms have been studied previously, the ability to independently and continuously vary both the physical properties and the degradation rates has not been demonstrated or disclosed in the literature. Since TPUs have been used in implanted medical devices for many years without and significant safety issues, the exemplary materials combine the excellent toxicological aspects of the component materials used in the polymer synthesis with the opportunity to provide tailorable properties and degradation rates.
• Poly(lactide-co-caprolactone) polyols with varying monomer ratios were converted to TPU using 4,4'-methylene dicyclohexyl diisocyanate-1 ,4- butanediol as the hard segment at 30-60 wt.% hard segment concentrations.
• the poly(lactide-co-caprolactone) polyols used include materials such as Perstorp's CapaTM 600422, consisting of a 2k molecular weight polyol with a composition of 88 caprolactone:12 lactide, on a molar basis.
• the initial synthesis, characterization and 8 week in vitro bioabsorption data is reported for exemplary bioabsorbable TPUs. The data provides initial results which indicate that independently controlling the physical and biodegradation properties with these materials is readily achievable.
• Biodegradable copolymers poly(lactide-co-caprolactone) polyols (Mn ⁇ 2000) composed of caprolactone and lactic acid units at varying ratios were used. These were random polymers, as verified by NMR. However, no stereocenter dyad analysis was made. Poly(lactide-co-caprolactone) polyols with 12.5 and 25.0% lactide are crystalline and those with 30.0 and 50.0% lactide contents are amorphous. HMDI, butanediol, and an aliphatic diisocyanate (Desmodur W) are used as well . Cotin 430 was employed as the reaction catalyst at 100ppm.
• TPU's were synthesized using typical aliphatic TPU lab polymerization procedures as follows:
• Blends were prepared by premixing the ingredients (polyol(s) and chain extender(s)) in an appropriately sized glass jar or by weighing the ingredients directly into a reactor can . If premixing was used, then all of the blend ingredients were weighed into a glass jar, the lid was tightened, and the contents were vigorously shaken to homogenize the blend.
• the required amount of polyol blend was poured into the reactor tin can (the reaction can). If weighing directly into a reactor can is the preferred procedure, then all of the blend ingredients were weighed into an appropriately sized reactor cans (a quart size tin can for 400-gram). The blend was placed in the oven to equilibrate at the temperature required for the reaction. The curing pans (Teflon® coated) were preheated to the temperature required for aging. The amount of aliphatic diisocyanate (Desmodur WTM) plus an estimated amount of drain residue was weighed into an appropriately sized can, and it was placed in the oven to equilibrate at the temperature required.
• Desmodur WTM aliphatic diisocyanate
• the reactor cans were removed from the oven(s) and place in the fume hood .
• a firmly mounted, air driven agitator was positioned approximately 1 ⁇ 4 inch from the bottom of the reactor can .
• the appropriate amount of diisocyanate was rapidly poured into the reaction can containing the polyol blend.
• a short time was allowed for the diisocyanate to drain out of the can.
• the catalyst was added and the start temperature was recorded. The exotherm temperature was monitored every 30 to 60 seconds.
• the preheated Teflon® coated pan were taken from the oven, the mixer was stopped and the reaction product was poured into the preheated pan .
• the biodegradation test for all samples is performed using the ASTM F1635 (Standard test method for in vitro degradation testing of hydrolytically degradable polymer resins and fabricated forms for surgical implants), as described above. After each time period (here 2 days, 1 week, 2, 4, 8, 12, 20, 28, 36 ... weeks) one sample is taken out and tested for tensile strength, elongation, molecular weight and weight loss. Only 8 weeks data (molecular weight, tensile and elongation data) for the samples based on poly(lactide-co-caprolactone) polyols is reported here. Thermal characterization of these materials using DSC is also reported.
• ASTM F1635 Standard test method for in vitro degradation testing of hydrolytically degradable polymer resins and fabricated forms for surgical implants
• the DSC curves (not reported here) exhibit endotherms right after the low temperature Tg which is usually attributed to enthalphic relaxation due to left over stress in these polymers. While not wishing to be bound by theory, this is somewhat expected with these materials because the thermodynamic incompatibility of the poly(lactide-co-caprolactone) polyols and the non-crystalline hard segment is reduced by incorporation of lactic acid units which may decrease the degree of phase separation and phase separation kinetics in these materials. This trend can also be deduced from the increase of the soft or mixed segment glass transition temperature as the lactic acid content is increased. Broad transitions (over 50°C) are observed for these materials and this range increased as the hard segment content is increased.
• Poly(lactide-co-caprolactone) polyols are classified by the lactic acid contents.
• the general chemical structure for the TPUs based on these materials is shown below in Structure 1 .
• a number of different polymers were prepared.
• the polymers synthesized and their thermal characterization (by DSC) are shown in Tables 2, 3, and 4.
• the results are categorized according to the amount of hard segment; 30, 45, 60%.
• Control formulations based on PCL (2000Mn) at 30 and 60% hard segment are also made and being tested.
• the thermal and biodegradation results for each set of materials are given in Tables. Not all the samples were tested for "hardness" so this property is reported whenever it is available, otherwise it is left blank.
• PLA content (%) is the polylactide content of the poly(lactide- co-caprolactone) polyol used in the formulation .
• Table 3 shows the PLA content (%) of various poly(lactide-co- caprolactone) polyols used in the Examples.
• the poly(lactide-co- caprolactone) polyols are identified by the (approximate) PLA content.
• TPU IDs reference the amounts of polyol PLA wt. % (1 st no.) and hard segment wt. % (2 nd no.) in the TPU.
• A12-30 is a TPU formed from POLYOL 12 with a soft segment PLA content of 12.5% and a hard segment content of 30%.
• TABLE 4 Polymer formulations and thermal properties for materials with 30-60 % hard segment content
• TABLE 6 show physical and biodegradation data for the A30-60 and A50-45 samples to demonstrate that similar biodegradation profiles can be achieved with very different initial tensile strength values.
• TABLE 7 shows physical and biodegradation data for the samples A50-30 and A25-45 to demonstrate that different biodegradation profiles with the same initial tensile strength values:
• the polymer is first hydrated and then breaking of the hydrolytically labile linkages takes place.
• the hydrophilic/hydrophobic balance of the composition determines the wetting rate and accordingly the degradation rate.
• the hydrolysis can be catalyzed with acidic and basic moieties or specific enzymes in the body.
• the degradation rates in these Examples are measured in buffered solution where the pH of the medium is maintained close to neutral and no enzymes are present. It is to be expected that the measured degradations rates in vitro may correspond to higher rates in vivo. Accordingly, if the specification provides a desired degradation rate based on in vivo comparisons, this can be reduced to compensate for the difference between in vivo and in vitro results.
• the hydrophobicity/hydrophilicity ratio of bioabsorbable polymers is a significant factor in the rate of the bioabsorption. Therefore, on this basis, as well as on the basis of the concentration more easily hydrolyzed ester groups, it can be expected that the TPUs which contain higher percent hard segment would degrade more slowly in the in vitro bioabsorption tests. The degradation data support this expected trend.

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