WO2014135727A1 - Nouveaux terpolymères aléatoires à base de d-lactide, l-lactide et ε-caprolactone - Google Patents

Nouveaux terpolymères aléatoires à base de d-lactide, l-lactide et ε-caprolactone Download PDF

Info

Publication number
WO2014135727A1
WO2014135727A1 PCT/ES2014/070156 ES2014070156W WO2014135727A1 WO 2014135727 A1 WO2014135727 A1 WO 2014135727A1 ES 2014070156 W ES2014070156 W ES 2014070156W WO 2014135727 A1 WO2014135727 A1 WO 2014135727A1
Authority
WO
WIPO (PCT)
Prior art keywords
lactide
caprolactone
iii
bismuth
comonomers
Prior art date
Application number
PCT/ES2014/070156
Other languages
English (en)
Spanish (es)
Inventor
Jorge FERNÁNDEZ HERNÁNDEZ
Aitor LARRAÑAGA ESPARTERO
José Ramón SARASUA OIZ
Original Assignee
Universidad Del País Vasco
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universidad Del País Vasco filed Critical Universidad Del País Vasco
Publication of WO2014135727A1 publication Critical patent/WO2014135727A1/fr

Links

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
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes
    • C08G63/82—Preparation processes characterised by the catalyst used
    • C08G63/823—Preparation processes characterised by the catalyst used for the preparation of polylactones or polylactides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/043—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • 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
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
    • C08G63/08—Lactones or 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
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes

Definitions

  • the present invention relates to the chemical synthesis of thermoplastic, bioabsorbable and biocompatible biopolymers for application preferably in the medical field and more especially to random terpolymers based on D-lactide, L-lactide and ⁇ -caprolactone with little or no crystallization capacity during hydrolytic degradation.
  • biodegradable polymers During the last decades the synthesis of biodegradable polymers has been stimulated by the need for new materials for applications in the medical field. These biomaterials are designed to degrade in a controlled manner over a predetermined period of time, decomposing into small non-toxic molecules that can be reabsorbed or excreted by the human organism, and, therefore, do not have to be removed clinically once their function but they must maintain their performance (mechanical properties and biocompatibility) during the time in which they are used.
  • absorbable homopolymers such as polyglycolide (PGA) or polylactides (PLAs)
  • PGA polyglycolide
  • PLAs polylactides
  • applications in the medical field of these thermoplastic elastomers required are included cell therapy for soft tissue reconstruction and use in the surgical field as implants, stents or catheters.
  • the conformation of reliable medical devices requires materials that have stability, durability and predictability of their macroscopic and microscopic properties.
  • materials that have stability, durability and predictability of their macroscopic and microscopic properties.
  • Through better control of the composition and microstructure, as well as molecular weight it is possible to make new thermoplastic materials with custom properties, which improve the properties of commercial absorbable polymers, being able to adapt their mechanical properties and degradation times to needs of specific medical applications.
  • the medical field requires highly flexible resistant biodegradable materials that degrade over a certain period of time and preferably have transition temperatures above 15 ° C.
  • the crystallization capacity of the most commonly used copolymers and terpolymers is still high and due to poor adjustments in the composition and underestimation of their sequence distribution are materials prone to structural changes during storage or hydrolytic degradation.
  • low molecular weight crystalline residues are formed in the degradation process that can remain in the human body for years, once the material has already lost its properties and has fulfilled its function
  • random terpolymers (R greater than 0.9) are synthesized in the present invention by polymerization of L-lactide and D-lactide, to provide consistency and mechanical strength to the material, and ⁇ -caprolactone to provide elastomeric character.
  • These materials show little or no crystallization capacity during storage or degradation thanks to the control of the average lengths of L-lactide or D-lactide and ⁇ -caprolactone. They are thermoplastic materials of different mechanical behaviors that exhibit a homogeneous degradation without the formation of crystalline residues of high hydrolytic resistance and that have a glass transition temperature greater than 15 ° C.
  • the present invention is directed to random terpolymers (R> 0.85) obtainable by mass polymerization (without solvent use) in a single stage of:
  • terpolymers can be synthesized in a single stage by adding the comonomers (I) to (III) at the same time.
  • the catalyst is added once the mixture has been melted and the medium has been inerted.
  • These polymers have a marked random character in the distribution of lactide and caprolactone units (short sequences of L-lactide, D-lactide and ⁇ -caprolactone).
  • sequences of L-lactide or D-lactide and of ⁇ -caprolactone have the ability to crystallize during degradation
  • the materials of the present invention exhibit little or no crystallization capacity during storage or degradation thanks to the control of average lengths of L-lactide or D-lactide and ⁇ -caprolactone.
  • They are thermoplastic materials of different mechanical behaviors that exhibit a homogeneous degradation without the formation of crystalline residues of high hydrolytic resistance and that have a glass transition temperature greater than 15 ° C.
  • the presence of L-lactide and D-lactide contributes to increase the consistency and mechanical strength of the material, and the presence of ⁇ -caprolactone contributes to providing elastomeric character.
  • random terpolymers are obtained by reacting a mixture of comonomers having a molar content of ⁇ -caprolactone between 5 and 30 mol% with respect to the total of comonomers (I), (II) and ( III). For values of less than 5%, the material becomes very susceptible to brittle breakage and its mechanical behavior resembles that of the most common semicrystalline homopolymers.
  • the glass transition temperature will be very low (less than 15 ° -20C) and although their elastomeric character is very high the consistency of these will be insufficient (very low elastic modules, ⁇ 5 MPa) being difficult to work with them at temperatures higher than their glass transition temperature, as is the case with the temperature of the human body (37 ° C).
  • random terpolymers are obtained by reacting a mixture of comonomers having a molar content of a ⁇ -caprolactone molar content between 5 and 25 mol% with respect to the total comonomers (I), (II ) and (III) and preferably having the same amount of L-Lactide and D-Lactide.
  • random terpolymers are obtained by reacting a mixture of comonomers having a molar content of a ⁇ -caprolactone molar content between 5 and 15 mol% with respect to the total comonomers (I), (II ) and (III).
  • Such polymers have exceptional properties for applications in which the stiffness of the terpolymers is important, being an alternative to the rigid biodegradable materials currently used that are very susceptible to brittle breakage (vitreous behavior) and / or have a high crystallization capacity during the degradation resulting in crystalline residues of low molecular weight that, due to their high hydrolytic resistance, can remain in the human body for years, once the material has already lost its properties and has fulfilled its function.
  • the random terpolymers are obtained by reacting a mixture of comonomers having a molar content of a ⁇ -caprolactone molar content between 15 and 30 mol% with respect to the total comonomers (I), (II ) and (III).
  • Such polymers have exceptional properties for applications in which the elastomeric properties of the terpolymers are important, being an alternative to the currently used elastomeric biodegradable materials that have a very low T g , presenting insufficient consistency, and / or have a high capacity of crystallization during degradation.
  • random terpolymers are obtained by reacting a mixture of comonomers having a molar content of L-lactide between 3 and 72%, preferably between 5 and 72% with respect to the total comonomers ( I), (II) and (III) and a D-lactide content between 3 and 72%, preferably between 5 and 72% of the total comonomers (I), (II) and (III).
  • random terpolymers are obtained by reacting a mixture of comonomers having a molar content of ⁇ -caprolactone (II) between 5 and 30% with respect to the total comonomers (I), (II) and (III) an L-lactide content between 3 and 72%, preferably between 5 and 72% of the total comonomers (I), (II) and (III) and a D-lactide content between 3 and 72%, preferably between 5 and 72% of the total comonomers (I), (II) and (III).
  • random terpolymers are obtained by reacting a mixture of comonomers in which the enantiomeric excess of L-lactide or D-lactide is greater than 5%, preferably greater than 7.5% and more preferably greater than 10%.
  • Another aspect of the present invention is the method of synthesis of the random terpolymers described above which consists in reacting the catalyst and the comonomers in a single stage:
  • the polymerization reaction proceeds by ring opening polymerization (ROP) being carried out in bulk at temperatures between 120 and 140 ° C for 2 or 3 days of reaction. Once the reaction is finished, it is necessary to remove impurities from the catalyst, oligomers and monomers that have not reacted. This is done by dissolution-precipitation in chloroform-methanol but there are other alternatives such as the use of other solvent-precipitating pairs or vaporization under pressure.
  • ROP ring opening polymerization
  • the polymerization reaction is carried out in a single stage by adding the comonomers at the same time, while the catalyst is added once the mixture has been melted and the medium has been inerted thus giving rise to random polymer structures (R> 0.85).
  • the polymerization reaction is carried out in a single step in the presence of a catalyst that is selected from the group consisting of bismuth 2-ethylhexanoate, bismuth hexanoate (BiHex 3 ), the triflate of bismuth (Bi (OTf) 3 ), bismuth diphenyl ethoxide (Ph 2 BiOEt), bismuth subsalicylate (BiSS) and bismuth triphenyl (Ph 3 Bi), more preferably from the group consisting of bismuth subsalicylate ( BiSS) and bismuth triphenyl (PH 3 Bi).
  • a catalyst that is selected from the group consisting of bismuth 2-ethylhexanoate, bismuth hexanoate (BiHex 3 ), the triflate of bismuth (Bi (OTf) 3 ), bismuth diphenyl ethoxide (Ph 2 BiOEt), bismuth subsalicylate (BiSS
  • the catalysts are used so that the molar ratio of the total monomers (I), (II) and (III) to the catalyst is between 250: 1 and 10,000: 1, preferably between 750: 1 and 2000 : 1, more preferably between 1000: 1 and 1500: 1 and the reaction is preferably carried out in an inert atmosphere, eg in an N 2 atmosphere.
  • the reaction is carried out at temperatures between 120 and 150 ° C, more preferably between 130 and 140 ° C and the reaction time is between 8 and 96 hours depending on the reaction temperature.
  • the reaction time can be between 48 and 72 hours and when the temperature is 140 ° C the reaction time can be between 32 and 48 hours.
  • Another aspect of the present invention relates to mixtures of one or more of the random terpolymers described above.
  • composite material is understood as those materials that are formed by mixing the terpolymers of the invention and one or more materials to achieve the combination of properties that cannot be obtained in the original materials.
  • Said composite materials are formed by two or more physically distinguishable and mechanically separable components and have several chemically distinct phases, completely insoluble to each other and separated by one inferred.
  • Examples of composite materials are those consisting of terpolymers of the invention with mechanical reinforcement, that is to say they comprise terpolymers of the invention and fibers or particles (inorganic fillers and nano-charges such as glass fibers, carbon fibers or carbon nanotubes; organic fillers).
  • composite materials are those comprising terpolymers of the invention and bioactive fillers such as bioactive inorganic particles (bioglass, hydroxyapatite etc.) or bioactive molecules such as growth factors (set of substances, most of a protein nature) that stimulate the cell proliferation by regulating the cell cycle by initiating mitosis and, in addition, regulating cell survival and stimulating cell migration, cell differentiation and even apoptosis) in order to improve cell activity and growth in the polymer matrix.
  • bioactive inorganic particles bioglass, hydroxyapatite etc.
  • bioactive molecules such as growth factors (set of substances, most of a protein nature) that stimulate the cell proliferation by regulating the cell cycle by initiating mitosis and, in addition, regulating cell survival and stimulating cell migration, cell differentiation and even apoptosis) in order to improve cell activity and growth in the polymer matrix.
  • composite materials are composite materials comprising terpolymers of the invention and antibiotic agents (phosphamycin, gentamicin, etc.) in order to improve the antibacterial activity of the polymer matrix.
  • medical devices or implants such as catheters; the probes; nerve guides (tubular grafts that bridge two ends of a damaged nerve); stents (devices of different designs, usually meshes, that are introduced into the coronary arteries (cases of atherosclerosis), esophagus (cases of esophageal stenosis) etc, and act by pointing at its wall); sutures, fixations, inserts and / or bone substitutes; the capsules for drug release, scaffolds or cell anchors (anchoring matrices of porous three-dimensional structure) comprising the random terpolymers described above.
  • Rigid terpolymers will preferably be used in hard tissues (bone tissues) and the most flexible terpolymers in soft tissues (cardiology, urology, etc.
  • plastics comprising the random terpolymers described above and other biodegradable and biocompatible polymeric materials together with additives for plastics such as flame retardants, antioxidants, foaming, plasticizers, ultraviolet light absorbers, antistatic, antibacterial and other additives for plastics such as those described in the Encyclopedia of Plastics (Volume 3). pp. 1-28.
  • additives for plastics such as flame retardants, antioxidants, foaming, plasticizers, ultraviolet light absorbers, antistatic, antibacterial and other additives for plastics such as those described in the Encyclopedia of Plastics (Volume 3). pp. 1-28.
  • the molar content of the set formed L-lactide and D-lactide influences stiffness, mechanical strength and consistency. If in an L-lactide- ⁇ -caprolactone copolymer we substitute D-lactide for e-caprolactone, the mechanical properties associated with the tension (elastic modulus and tensile stress) are increased and the elongation at break is somewhat reduced. The glass transition temperature of the material is increased. On the other hand, by replacing L-lactide with D-lactide, we managed to break the microstructural order of L-lactide units by limiting their crystallization capacity. The molar content in ⁇ -caprolactone can vary between 5 and 30% depending on the elastomeric properties required.
  • ⁇ -caprolactone When the molar content of ⁇ -caprolactone is between 5 and 15 mol% with respect to total comonomers (I), (II) and (III). Said terpolymers have exceptional properties for applications in which the stiffness of the terpolymers is important while when the molar content of ⁇ -caprolactone is between more than 15 and 30 mol% with respect to the total comonomers (I), (II) and (III) the terpolymers have exceptional properties for applications in which the elastomeric properties of the terpolymers are important, being an alternative to the currently used elastomeric biodegradable materials that have a very low T g , presenting insufficient consistency, and / or have a high crystallization capacity during degradation.
  • the materials of the present invention exhibit little or no crystallization capacity during their degradation thanks to the control of the average lengths of L-lactide or D-lactide and ⁇ -caprolactone. They are thermoplastic materials of different mechanical behaviors that exhibit a homogeneous degradation without the formation of crystalline residues of high hydrolytic resistance.
  • Figure 5 Representation of the neperian logarithm of the molecular weights by weight (Mw) versus the degradation time to obtain the degradation kinetic constants of each poly (lactide / £ -caprolactone) (PLCL) used as an example.
  • Figure 8 Representative stress-strain curves of poly (lactide / £ - caprolactone) (PLCLs) synthesized in Examples 1-4.
  • random terpolymers are understood as the polymers resulting from the ring opening reaction of three monomers in which the distribution of the repeating units derived from said monomers along the polymeric chain has a character markedly random, that is, very close to the Bernouilli statistical distribution and more specifically terpolymers having a value of R, determined as explained below, greater than 0.85, more preferably greater than 0.90 and still more preferably greater than 0.95.
  • a material has an elastomeric character when it shows an elastic behavior, that is, when it is capable of undergoing reversible deformations when it is subject to the action of external forces and to recover the original shape if these external forces They are removed.
  • Materials with an elastomeric character also typically have high values of strain at break, have no yield point (creep stress) and typically have a high elastic recovery.
  • thermoplastic material is understood to be that which, at relatively high temperatures, becomes plastic, deformable or flexible, melts when heated and hardens in a glass transition state when it is allowed to cool sufficiently.
  • Thermopastic materials have a thermodynamic pseudotransition when heated (the glass transition temperature (T g ) being the temperature at which said thermodynamic pseudotransition occurs).
  • Thermoplastic polymers differ from thermosetting polymers or thermofixes in that after heating and molding they can overheat and form other objects, while in the case of thermosets or thermofixes, after initial cooling, their shape does not change when heated but they are combusted before achieving a change of form.
  • enantiomeric excess is understood as the percentage obtained by performing the following arithmetic operation:
  • the consistency of a material at the working temperature of said material is understood as the ability of the material to retain its shape at said temperature without softening so that it maintains its ability to act as a mechanical support.
  • mechanical strength of a material is understood as the mechanical properties associated with the tension and in particular the elastic modulus (or the 2% secant modulus) and the breaking stress.
  • catalyst is understood as those metal compounds and enzymes that make possible the polymerization reactions of the cyclic esters.
  • Particularly suitable as catalysts in the present invention are organic bismuth salts such as bismuth 2-ethylhexanoate, bismuth hexanoate (BiHex 3 ), bismuth triflate (Bi (OTf) 3 ), bismuth diphenyl ethoxide (Ph 2 BiOEt), bismuth subsalicylate (BiSS) and bismuth triphenyl (Ph 3 Bi) and even more preferred bismuth subsalicylate (BiSS) and bismuth triphenyl (Ph 3 Bi).
  • organic bismuth salts such as bismuth 2-ethylhexanoate, bismuth hexanoate (BiHex 3 ), bismuth triflate (Bi (OTf) 3 ), bismuth diphenyl ethoxide (Ph 2 BiOEt), bismuth subs
  • cell anchoring to porous polymeric matrices is understood on the surface of which one or more cells are joined by any means of attachment including covalent, non-ionic bonds, Van der Waals forces.
  • medical implants are understood as any medical device manufactured to replace a missing biological structure, supplant a damaged biological structure, or improve an existing biological structure.
  • Medical implants are man-made devices, unlike transplants, which are biomedical tissues. Examples of medical implants are pacemakers, cochlear implants, drug delivery devices, cannulas and stents. Determination of the average length of Lactide and ⁇ -caprolactone sequences
  • the average lengths of Lactide and ⁇ -caprolactone sequences are calculated from the areas of the signals corresponding to the methine groups of the repeating units derived from the lactides (-CH-) and the average value of the signal areas corresponding to the methylenes of the repeating units derived from ⁇ -caprolactone ( ⁇ and a-CH 2 ) in proton nuclear magnetic resonance spectra ( 1 H-NMR).
  • the signal corresponding to the methine of the repeating units derived from the lactide is found at chemical shifts between 5.0 ppm and 5.3 ppm. Due to the existence of HH couplings there is an overlap of the signals corresponding to the repeat units that derive from the lactide and that are adjacent to other repeat units that derive from the lactide on the one hand and the signals corresponding to the repeat units that derive from the lactide and that are adjacent to units Repeat derived from ⁇ -caprolactone on the other hand. Therefore, the set of both signals is integrated together and the resulting area is designated as A.
  • the signal of the methylene protons in ⁇ is found in the area with chemical shifts around 4.1 ppm being divided into 2 groups: a) the one with the greatest displacement (with an area B) corresponds to the protons of the ⁇ -methylenes of those ⁇ -caprolactone repeat units that have, with the carbonyl end of ⁇ -caprolactone, a lactide repeat unit and b) the one with the lowest displacement (with an area C) corresponds to the protons of ⁇ -methylenes of those ⁇ -caprolactone repeat units that have, ⁇ -caprolactone attached to the carbonyl end, a ⁇ -caprolactone repeat unit.
  • the signal of the protons of the methylenes in ⁇ is found in the zone with displacements around 2.3 being also divided into 2 groups: the one with the greatest displacement (with an area D) corresponds to the protons of the methylenes in ⁇ of those ⁇ -caprolactone repeating units that have, together with the ether end of ⁇ -caprolactone, a repeating unit of lactide and the one with the least displacement (with an area D) corresponds to the protons of the methylenes in ⁇ of those ⁇ -caprolactone repeating units that have a ⁇ -caprolactone repeating unit attached to the ether end of ⁇ -caprolactone.
  • the average length of Lactide and ⁇ -caprolactone (/ ⁇ ) sequences, the average Bernoulli (/ ⁇ ) random-Bemouiii ⁇ sequences and the random character (R) were calculated by applying the following equations:
  • the parameters LA, CL L A, CL C L and CL can be calculated from areas A, B, C, D and E as follows:
  • LA L A is a parameter proportional to the number of lactide repeat units of the copolymer having an adjacent unit of lactide and LA C L is a parameter proportional to the number of repeat units of lactide of the copolymer having an adjacent unit of ⁇ - caprolactone What is determined is the sum of LA L A and
  • CL L A copolymer ⁇ -caprolactone repeat units having an adjacent lactide unit
  • LA C L number of copolymer lactide repeat units having an adjacent ⁇ -caprolactone unit
  • [CL] CL / (LA + CL)
  • the average length of the lactide / L A repeat unit sequences and the average length of the ⁇ -caprolactone / C i_ repeat unit sequences can be calculated.
  • the synthesis is carried out at 140 ° C in a 50mL balloon with magnetic stirring and with a thermocouple for temperature control.
  • 12.50 g of L-lactide, 10.00 g of m-lactide and 2.50 g of ⁇ -caprolactone are weighed and added to the balloon.
  • the mixture is melted and a gentle flow of nitrogen is applied for half an hour to achieve an inert atmosphere in the medium.
  • 0.0430g of bismuth subsalicylate (BiSS) is added and the reaction time is counted.
  • the magnetic stirring is maintained at 100 rpm.
  • the balloon is removed from the oil bath and allowed to cool to room temperature. It is necessary to remove impurities from the catalyst, oligomers and monomers that have not reacted, and, for this reason, dissolve in chloroform and subsequently precipitate in methanol.
  • the synthesis is carried out at 140 ° C in a 50mL balloon with magnetic stirring and with a thermocouple for temperature control. 15.00 g of L-lactide, 6.25 g of m-lactide and 3.75 g of ⁇ -caprolactone are weighed and added to the balloon. The mixture is melted and a gentle flow of nitrogen is applied for half an hour to achieve an inert atmosphere in the medium. After that time, 0.0435g of bismuth subsalicylate (BiSS) is added and the reaction time is counted. The magnetic stirring is maintained at 100 rpm.
  • BiSS bismuth subsalicylate
  • the balloon is removed from the oil bath and allowed to cool to room temperature. It is necessary to remove impurities from the catalyst, oligomers and monomers that have not reacted, and, for this reason, dissolve in chloroform and subsequently precipitate in methanol.
  • the terpolymers of Examples 1 to 4 were analyzed by Differential Scanning Calorimetry (DSC), to obtain information on their thermal transitions related to their structure and morphology, and Size Exclusion Chromatography (SEC-GPC), to obtain their distribution of molecular weights Nuclear Magnetic Resonance Spectroscopy ( 1 H-NMR) was used to confirm the composition and sequence distribution of the polymers obtained.
  • DSC Differential Scanning Calorimetry
  • SEC-GPC Size Exclusion Chromatography
  • 1 H-NMR Nuclear Magnetic Resonance Spectroscopy
  • PBS phosphate buffered solution
  • AH m enthalpy of fusion
  • T m melting temperature
  • molecular weight distribution molecular weight by weight and polydispersity index
  • Tables 1 and 2 provide the results of the characterization using 1 H-RM N (composition and microstructural parameters) and molecular weight measurements of the poly (lactide / £ -caprolactone) (PLCLs) synthesized in Examples 1-4 . As you can see the sequence distribution is random and the random character (R) is approximately 1.
  • the molecular weights of the terpolymers synthesized in Examples 1-4 were measured by size exclusion chromatography (SEC or GPC) in a Waters 1515 equipped with two Styragel columns calibrated with polystyrene standards. Chloroform was used as eluent, the flow being 1 ml / min. From the molecular weight distribution the average molecular weights in number (M n ), in weight (M w ) and the polydispersity index (ratio) were obtained
  • composition of the terpolymers expressed as a percentage of molar content of ⁇ -caprolactone and lactide is obtained from the 1 H-NMR spectrum. Since it is impossible to offer the exact content of L-Lactide and D-Lactide (they are indistinguishable in the NMR spectrum) approximate values are given under the assumption of an equal reactivity of L-Lactide and D-Lactide. Under this assumption and taking into account the L-LA / D-LA ratio of the feed, we can obtain its molar fraction in the polymer because we know the content of caprolactone [CL] and lactide [LA]. Subsequently we obtain approximate values of the sequence lengths of L-LA and D-LA using the following formula
  • the structural parameters / L-LA and ta- LA are approximate values of the average sequence lengths of L-Lactide and D-Lactide obtained under the assumption of an equal reactivity of L-Lact
  • EXAMPLE 5 Thermal analysis during degradation of poly (lactide / £ - caprolactone) (PLCLs) synthesized in examples 1-4
  • the equipment used for scanning differential calorimetry analysis is a DSC Q200 from the calibrated TA Instruments commercial house with Indian and sapphire patterns. A sample between 5 and 9 mg is cooled to -85 ° C and heated to 185 ° C at 20 ° / min. During this first scan, information about the current physical and morphological state of the sample is obtained.
  • the glass transition temperature of the material (T g ), enthalpy relaxation ⁇ (J g "1 ), the enthalpy of fusion ⁇ (J g " 1 ) and the temperature of temperature are obtained from the calorimetric flow vs. temperature curve.
  • crystalline fusion (T m ) of the polymer is obtained. Subsequently, through a second scan, information is obtained on the properties of the polymer, independent of the thermal history.
  • Figure 1 shows the curves of the first differential scanning calorimetry (DSC) scan at different degradation times corresponding to the PLCL 008515 synthesized in Example 1. It can be seen how as the degradation progresses the transition temperature of the material, which is initially of 28.7 ° C, decreases.
  • the PLCL 008515 remains amorphous throughout the study and no fusion is seen by not having crystallizable sequences of L-lactide being the sequences of ⁇ -caprolactone short enough to not be able to crystallize.
  • a small enthalpy relaxation associated with the glass transition temperature can be distinguished.
  • Figure 2 shows the curves of the first sweep differential scanning calorimetry (DSC) at different degradation times corresponding to the PLCL 502525 synthesized in example 2. It can be seen how as the degradation progresses the transition temperature of the material, which initially is of 20.8 ° C, decreases.
  • the PLCL 502525 remains amorphous throughout the study and is not appreciated no fusion associated with the crystallizable sequences of L-lactide and ⁇ -caprolactone since their sequence lengths are short enough.
  • Figure 3 shows the curves of the first scanning differential scanning calorimetry (DSC) at different degradation times corresponding to the PLCL 504010 synthesized in example 3. It can be seen how as the degradation progresses the transition temperature of the material, which is initially of 38.0 ° C, decreases.
  • the PLCL 504010 remains amorphous until day 49 of degradation, in which a small fusion (T m ⁇ 80 ° C) associated with crystallizable sequences of L-lactide is observed, which increases until reaching a value of about 8 J / g on the final day of the study.
  • T m ⁇ 80 ° C small fusion associated with crystallizable sequences of L-lactide
  • Figure 4 shows the curves of the first scan of differential scanning calorimetry (DSC) at different degradation times corresponding to the PLCL 602515 synthesized in Example 4. It can be seen how as the degradation progresses the transition temperature of the material, which is initially of 36, 1 ° C, decreases. PLCL 602515 remains amorphous until day 35 of degradation, in which a small fusion (T m ⁇ 80 ° C) associated with crystallizable L-lactide sequences is observed, which increases until reaching a value of about 18 J / g on the final day of the study. It should be noted the presence of a marked enthalpy relaxation, lower than that of PLCL 504010, associated with the glass transition temperature. The intensity of the peak falls to high degradation times as the glass transition temperature of the material decreases.
  • DSC differential scanning calorimetry
  • Table 3 collects the evolution data during the study of degradation of molecular weights in weight (M w ), polydispersity index (IP) and thermal properties, obtained in two DSC scans, of the poly (lactide / £ - caprolactone) (PLCLs) synthesized in examples 1-4.
  • EXAMPLE 6 Evolution of molecular weights and calculation of degradation kinetics during degradation of poly (lactide / £ -caprolactone) (PLCLs) synthesized in examples 1-4
  • Figure 5 shows the evolution of the Neperian logarithm of the molecular weight by weight (M w ) versus the degradation time of the PLCLs synthesized in Examples 1-4.
  • the Relationship between the Neperian logarithm of molecular weight in weight and time is approximated by the equation:
  • the values of the kinetic constant K Mw were calculated from the slope of the adjustment curve of the molecular weight data versus time in the first 35 days of study for the PLCLs 008515 and 502525 and in the first 49 days for the PLCLs 504010 and 602515, since at higher times surface erosion becomes the dominant mechanism. Based on these results, the order of degradation rate is PLCL 008515> PLCL 502525> PLCL 602515> PLCL 504010. These PLCLs in Examples 1-4 show rapid degradation.
  • the PLCL 008515 has a kinetic constant of 0.066 days "1 and an average life time of 10.5 days.
  • the PLCL 502525 has a kinetic constant of 0.056 days " 1 and an average life time of 12.4 days.
  • the PLCL 504010 has a kinetic constant of 0.030 days "1 and an average life time of 23.1 days.
  • the PLCL 602515 has a kinetic constant of 0.040 days " 1 and an average life time of 17.3 days.
  • EXAMPLE 7 Weight loss and water absorption during degradation of poly (lactide / £ -caprolactone) (PLCLs) synthesized in examples 1-4
  • the weight loss or remaining weight of polymer (% RW) and water absorption (% WA) values were obtained at different degradation times from the wet weights (W w ), measured immediately after taking the samples and remove surface water, wrapping the sample in blotting paper and measuring dry weight (W d ), carried out after subjecting the samples to a drying process overnight followed by drying in a vacuum oven (800-900 bar) at room temperature for 24 hours, taking into account the initial weight of each sample (W 0 ) and using the equations :.
  • Figure 6 shows the evolution of the remaining weight during the degradation of the PLCLs synthesized in Examples 1-4.
  • Figure 7 shows the evolution of water absorption during the degradation of PLCLs synthesized in Examples 1-4.
  • Biomaterials begin to lose mass when they reach a molecular weight by weight limit. At that time the solubility of the oligomers is favored and the water absorption is already very high.
  • the weight loss of the PLCL 008515 and the PLCL 502525 begins on day 35 when their respective M w are 8400 and 1 1800 g / mol.
  • the PLCL 504010 and the PLCL 602515 the weight loss is evident on day 56 of degradation, in which their respective M w are 12000 and 9400 g / mol.
  • the mechanical tests of the non-degraded samples and of the submerged samples for 7, 14 and 21 days belonging to the PLCLs synthesized in Examples 1-4 were carried out in an Instron 5565 unit at a speed of 10 mm min "1 . Tests were carried out with a controlled temperature of 21 ⁇ 2 ° C and a relative humidity of 50 ⁇ 5% according to ISO 527-3 / 1995.
  • the mechanical properties offered correspond to average values of at least 5 specimens. from 150-200 ⁇ films prepared by him method of dissolution-evaporation in chloroform followed by a thermal treatment with rapid cooling.
  • Figure 8 shows the most representative stress-strain curves of the PLCLs synthesized in Examples 1-4.
  • the PLCL 502525 has a clearly elastomeric behavior (2% secant modulus of 5.7 MPa and 994% elongation at break) without the presence of a creep point.
  • the PLCL 008515 has a 2% secant module of 146.5 MPa and an elongation at break of 361%.
  • the PLCLs synthesized in Examples 3 and 4 are more rigid with secant modules of 336.7MPa and 331.3 MPa, respectively.
  • the PLCL 504010 has a more vitreous behavior with an elongation at break of 59%. Instead, the PLCL 602515 deforms up to 230%.
  • Table 4 shows the mechanical properties (2% secant modulus, creep stress, breaking stress, elongation at break and elastic recovery) of the PLCLs synthesized in Examples 1-4 at different degradation times.
  • the PLCL 008515 undergoes a small change in its properties towards a more rigid behavior, related to the small enthalpy relaxation observed in the DSC scan ( Figure 1). Then, as the glass transition temperature of the material decreases and the mobility of the chains increases, the PLCL 008515 gains elastomeric character but suffers a deterioration in its mechanical properties (2% secant modulus and tensile stress) The PLCL 502525 could only be tested prior to the start of the degradation study. After a week submerged at 37 ° C in PBS, it lost consistency and it was impossible to carry out mechanical tests.
  • the PLCL 504010 undergoes a significant change in its properties towards a more rigid behavior, related to the enthalpy relaxation observed in the DSC scan (Figure 3). Elongation at break goes from 59% to 4%. On day 14, mechanical tests could no longer be carried out due to the fragility of the material.
  • the PLCL 602515 undergoes a change in its properties towards a more rigid behavior, related to the enthalpy relaxation observed in the DSC scan ( Figure 4).
  • the mechanical properties 2% secant modulus, tensile strength, elongation at breakage
  • PLCL 502525 became too viscous during degradation and no mechanical tests could be made due to its lack of consistency.
  • the PLCL 504010 became very fragile from day 7 of degradation and mechanical tests could not be carried out at other degradation times.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Polymers & Plastics (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Vascular Medicine (AREA)
  • Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Polyesters Or Polycarbonates (AREA)
  • Materials For Medical Uses (AREA)

Abstract

La présente invention concerne des terpolymères aléatoires à base de D-lactide, L-lactide et ε-caprolactone à capacité de cristallisation durant la dégradation hydrolytique réduite ou nulle.
PCT/ES2014/070156 2013-03-04 2014-03-03 Nouveaux terpolymères aléatoires à base de d-lactide, l-lactide et ε-caprolactone WO2014135727A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES201330302A ES2504666B1 (es) 2013-03-04 2013-03-04 NUEVOS TERPOLÍMEROS ALEATORIOS A BASE DE D-LACTIDA, L-LACTIDA y E-CAPROLACTONA
ESP201330302 2013-03-04

Publications (1)

Publication Number Publication Date
WO2014135727A1 true WO2014135727A1 (fr) 2014-09-12

Family

ID=51490667

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/ES2014/070156 WO2014135727A1 (fr) 2013-03-04 2014-03-03 Nouveaux terpolymères aléatoires à base de d-lactide, l-lactide et ε-caprolactone

Country Status (2)

Country Link
ES (1) ES2504666B1 (fr)
WO (1) WO2014135727A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104910355A (zh) * 2015-05-21 2015-09-16 常州大学 一种应用于生产聚乙醇酸的铋类催化剂
CN110204697A (zh) * 2019-06-25 2019-09-06 苏州大学 制备L-丙交酯和ε-己内酯无规共聚物的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100093946A1 (en) * 2008-10-11 2010-04-15 Orbusneich Medical, Inc. Bioabsorbable Polymeric Compositions and Medical Devices
US20100291175A1 (en) * 2009-05-14 2010-11-18 Abbott Cardiovascular Systems Inc. Polymers comprising amorphous terpolymers and semicrystalline blocks

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100093946A1 (en) * 2008-10-11 2010-04-15 Orbusneich Medical, Inc. Bioabsorbable Polymeric Compositions and Medical Devices
US20100291175A1 (en) * 2009-05-14 2010-11-18 Abbott Cardiovascular Systems Inc. Polymers comprising amorphous terpolymers and semicrystalline blocks

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
J. FERNANDEZ ET AL.: "A new generation of poly(lactide/ epsilon-caprolactone) polymeric biomaterials for application in the medical field", JOURNAL OF BIOMEDICAL MATERIALS RESEARCH A, 2013, pages 1 - 12 *
J. FERNANDEZ ET AL.: "Effects of chain microstructures on mechanical behavior and aging of a poly(L-lactide-co -epsilon -caprolactone) biomedical thermoplastic-elastomer", JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS, vol. 12, 2012, pages 29 - 38 *
J. FERNANDEZ ET AL.: "Synthesis and characterization of poly(L-lactide/epsilon -caprolactone) statistical copolymers with well resolved chain microstructures", POLYMER, vol. 54, 2013, pages 2621 - 2631 *
M. SRISA-ARD ET AL.: "Synthesis and characterization of a random terpolymer of L-lactide, epsilon-caprolactone and glycolide", POLYMER INTERNATIONAL, vol. 50, 2001, pages 891 - 896 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104910355A (zh) * 2015-05-21 2015-09-16 常州大学 一种应用于生产聚乙醇酸的铋类催化剂
CN110204697A (zh) * 2019-06-25 2019-09-06 苏州大学 制备L-丙交酯和ε-己内酯无规共聚物的方法
CN110204697B (zh) * 2019-06-25 2021-11-16 苏州大学 制备L-丙交酯和ε-己内酯无规共聚物的方法

Also Published As

Publication number Publication date
ES2504666B1 (es) 2015-09-04
ES2504666A1 (es) 2014-10-08

Similar Documents

Publication Publication Date Title
ES2375637T3 (es) Poli(éteres-ésteres) resorbibles y su utilización para la producción de implantes médicos.
ES2382034T3 (es) Composiciones de poliéster, procedimientos de preparación de dichas composiciones y productos formados a partir de las mismas
Xue et al. Biodegradable shape-memory block co-polymers for fast self-expandable stents
ES2305512T3 (es) Copolimeros biodegradables de varios bloques, segmentados y de fases separadas.
ES2212602T3 (es) Poliuretano biomedico, su preparacion y uso.
ES2628921T3 (es) Copolímeros absorbables segmentados, semicristallinos poli (lactida-co-epsilon-caprolactona)
ES2217670T3 (es) Copoliesteres con una inestabilidad hidrolitica minimizada y copolimeros cristalinos absorbibles derivados.
ES2537307T3 (es) Copolímero de bloque biocompatible, degradable
EP3082888B1 (fr) Compositions de mélanges polymères absorbables à base de copolymère préparées à partir d'initiateurs de polymérisation mono- et bi-fonctionnels, procédés de traitement, et dispositifs médicaux associés
Smola et al. Bioresorbable terpolymers based on L-lactide, glycolide and trimethylene carbonate with shape memory behaviour
Wang et al. Synthesis, characterization and surface modification of low moduli poly (ether carbonate urethane) ureas for soft tissue engineering
Kupka et al. Solvent free synthesis and structural evaluation of polyurethane films based on poly (ethylene glycol) and poly (caprolactone).
SG184102A1 (en) Biodegradable and biocompatible shape memory polymers
Bachtiar et al. Structure-property relationships in 3D-printed poly (l-lactide-co-ε-caprolactone) degradable polymer
ES2504666B1 (es) NUEVOS TERPOLÍMEROS ALEATORIOS A BASE DE D-LACTIDA, L-LACTIDA y E-CAPROLACTONA
ES2809537T3 (es) Materiales compuestos biocompatibles anhidros
ES2329329B1 (es) Pasta termoplastica para la reparacion tejidos vivos.
JP2008222768A (ja) 分岐型生分解性ポリエステル及びその製造方法
ES2266775T3 (es) Copolimeros de bloque para articulos quirurgicos.
JP6851990B2 (ja) 長期吸収特性を呈する半結晶性のラクチドとε−カプロラクトンとのセグメント化コポリマーから製造された新規な発泡体及びフィルムに基づく吸収性医療用装置
PL230303B1 (pl) Sposób wytwarzania bioresorbowalnych i biokompatybilnych elastomerów termoplastycznych, wykazujących pamięć kształtu, do zastosowań biomedycznych
Dobrzynski et al. Synthetic biodegradable medical polyesters: poly (trimethylene carbonate)
ES2732707T3 (es) Formulación polimérica semicristalina y de rápida absorción
JP7319466B2 (ja) ブロック共重合体
ES2311542T3 (es) Resina polimerica absorbible de gran consistencia.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14759814

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14759814

Country of ref document: EP

Kind code of ref document: A1