PL235484B1 - Method for producing bioresorbable polymer materials with controlled degree of reticulation, for medical applications - Google Patents

Description

The subject of the invention is a method of producing biocompatible and bioresorbable polymer materials for medical applications with increased mechanical strength.

Biodegradable polymers, and especially aliphatic copolymers obtained by ring-opening polymerization (ROP) of cyclic lactides, lactones or six-membered carbonates, are known and valuable biodegradable biomaterials used for years in modern surgery in the form of temporary implants. These materials are also used to form porous, three-dimensional scaffolds used as a substrate for cell colonization in tissue engineering techniques or in the formation of various drug carriers in the processes of their controlled release.

In orthopedic and trauma surgery applications, polymer bioresorbable implants have become quite common to stabilize damaged bones. The undoubted advantage of implanted items made of bioresorbable materials is the avoidance of interference with the patient's body, associated with the removal of this object from the body, required in the case of implants made of metal alloys, ceramics or other non-resorbable materials. The use of implants made of bioresorbable materials in orthopedics and in many maxillofacial or vascular surgery procedures is often limited by the insufficient mechanical strength of the implanted elements, which deteriorates quickly from the first weeks after implantation into the patient's body due to the ongoing degradation.

Scientific literature reports on chemically cross-linked poly (lactide) obtained by reacting a polymer melt with triallyl isocyanurate and dicumyl peroxide (S. Yang, Z.-H. Wu, W. Yang, M.-B. Yang Polymer Testing 27 (2008) 957-963). The obtained materials showed higher tensile strength and thermal stability as well as lower melting point. At the same time, these materials were brittle and the cross-linking of the material was carried out in an additional step, and moreover in the melt, where exposure to high temperature and high shear in processing machines promotes the degradation of polyesters. A similar strategy of cross-linking polylactide with triallyl isocyanurate was also used in another work (T. M. Quynh, H. Mitomo, N. Nagasawa, Y. Wada, F. Yoshii, M. Tamada European Polymer Journal 43 (2007) 1779-1785). Films obtained from mixtures of triallyl isocyanurate with PLLA or PDLA were exposed to β radiation at various doses. In the materials modified in this way, the gel fraction depended on the radiation dose. Cross-linking of polylactides resulted in a drop in melting point, however the material became harder and more brittle at lower temperatures. A similar method was used later ((Piotr Rytlewski, Rafał Malinowski, Krzysztof Moraczewski, Marian Żenkiewicz Radiation Physics and Chemistry 79 (2010), 1052-1057; R. Malinowski, P. Rytlewski, M. Żenkiewicz, Archives of Materials Science and Engineering 49 ( 2011) 25-32). The authors prepared mixtures of PLA with isocyanurate in the form of granules or extrudates, and then exposed to high-energy β radiation (approx. 10 MeV), which initiated cross-linking of the PLA mixture with isocyanurate. In this case, an increase in the glass transition temperature was described, while the materials obtained showed limited or even no flow. A slightly different strategy was adopted by the authors of another work (AO Helminen, H. Korhonen, JV Seppala J. Polym. Sci. A Polym. Chem., 41 (2003) 3788-3797) who prepared resorbable poly (ester-anhydride) networks In the first stage they obtained telechelic oligomers of ε-caprolactone, L-lactide and D, L-lactide, which in the second stage were functionalized succinic anhydride, then reacted with methacrylic anhydride. The material prepared in this way was cross-linked in a radical reaction initiated with dibenzoyl peroxide at a temperature of 120 ° C. The cross-linked material exhibited a glass transition temperature about 10 ° C higher than the oligomeric intermediate. In contrast, in vitro degradation tests showed complete degradation of the network within 4 days. The same authors also developed a method of solvent-free cross-linking of (3-isocyanatopropyl) triethoxysilane-functionalized oligomeric polylactide in an acid-catalyzed reaction in the presence of water (A. Helminen, H. Korhonen, J.V. Seppala Polymer 42, (2001) 3345-3353). The obtained materials, after the final cross-linking, were characterized by high mechanical strength and biodegradability. The chemical cross-linking method has also been used in the preparation of cross-linked poly (D, L-lactide-co-trimethylene) carbonate (R.F Storey, S.C. Warren, C.J. Allison, A.D. Puckett Polymer 38 (1997) 6295-6301). The authors used a multi-step synthesis with consecutive steps; (i) preparation of a triamine poly (D, L-lactide-trimethylene co-carbonate) prepolymer, (ii) functionalization of the terminal groups with methacryloyl chloride, and (iii) radical crosslinking of methacrylate groups. Also described in the scientific literature

PL 235 484 B1 preparation of reinforced poly (lactide) by mixing and reacting with cross-linked polyurethane (G.-C. Liu, Y.-S. He, J.-B. Zeng, Y. Xua, Y.-Z. Wang I Polym. Chem., 2014, Advance Article DOI: 10.1039 / C3PY01649H). The cross-linked material was formed in the process of reactive extrusion, and the obtained material was characterized by an approx. 30-fold increase in mechanical properties in relation to PLA. In contrast to chemical cross-linking, the scientific literature also describes examples of the formation of amphiphilic networks and physically cross-linked gels (X. Fan, M. Wang, D. Yuan, C. He Langmuir, 29 (2013) 14307-14313). The hydrophilic poly (ethylene glycol) monoacrylate and hydrophobic copolymers: poly [ethylene glycol-block- (L-lactide) monoacrylate] and poly [ethylene glycol-block- (D-lactide)] monoacrylate were crosslinked, initiating the radical reaction of acrylate groups and favoring physical interactions and the formation of a stereocomplex between poly (Li D-lactides).

In the above-mentioned examples, however, multi-stage methods were used, most often using toxic cross-linking initiators or ionizing radiation causing degradation of the material itself, and thus reducing the mechanical properties of the final material. Another solution was to introduce, at the stage of synthesis, non-degradable fragments into the polymer network.

The scientific literature also mentions the formation of branched and cross-linked copolymers in the copolymerization process of L-lactide or c-caprolactone with benzyl carbonate in the presence of tin octanoate as an initiator in the process carried out at temperatures exceeding 135 ° C (RF Storey, BD Mullen, KM Melchert J Macromol. Sci. - Pure Appl. Chem., A38 (2001) 897-917) (the work does not indicate that the degree of cross-linking of the materials obtained can be controlled). In the course of copolymerization carried out at lower temperatures, formation of corresponding soluble copolymers is observed.

Unexpectedly, it turned out that the method of producing biocompatible and bioresorbable (copolymers for medical applications, which is the subject of the invention, allows to obtain polymeric materials that are characterized by increased mechanical strength, compared to the previously known, widely accepted and used synthetic polymer materials constituting (co ) polymers of lactides, glycolide, ε-caprolactone or cyclic six-membered carbonates and natural materials such as poly (3-hydroxyalkanoate) y, without disturbing the biocompatibility of the synthesized copolymer and without additional cross-linking reactions. , a shaped medical device ready for use, and the process of its production can be controlled by the selection of an appropriate cross-linking agent and its amount / share in the copolymer formed, as well as the temperature of copolymerization so as to obtain according to the invention, the material or the finished product (implant) was characterized by mechanical, processing and biodegradation properties allowing, in particular, its use in orthopedics, trauma or maxillofacial surgery, in the form of screws or plates for osteosynthesis.

The method of producing bioresorbable polymeric materials with a controlled degree of cross-linking for medical applications, according to the invention, consists in the fact that it is obtained in the process of copolymerization of a cross-linking monomer, which is an ester-functional cyclic carbonate, i.e. 5-methyl-2-oxo-1 acid ester. , 3-dioxane-5-carboxylic acid of general formula I, wherein R is a straight or branched alkyl group with a carbon number of 1 to 8, halogenated alkyl, 2-tert-butoxy-2-oxoethyl, preferably 5-methyl- (2-tert-butoxy-2-oxoethyl) 2-oxo-1,3-dioxane-5-carboxylate, wherein the copolymerization is carried out in bulk or in a solvent in the presence of an initiator and / or a catalyst selected from the group consisting of acetylacetonates, alkyls , halides, alcoholates and / or triflates of zircon (IV), iron (III), titanium (IV) and / or scandium (III).

Preferably according to the invention, a cyclic six-membered carbonate containing a 2-tert-butoxy-2-oxoethyl substituent, i.e. (2-tert-butoxy-2-oxoethyl) 5-methyl-2-oxo-1,3-dioxane-5-carboxylate is used. which is copolymerized with lactide (s) and / or glycolide and / or ε-caprolactone and / or cyclic six-membered carbonates.

In the process of the invention, an initiator with proven activity in transesterification processes is used, selected from the group consisting of acetylacetonates, alkyls, halides, zirconium (IV), titanium (IV), and / or scandium (III) alkoxides, preferably zirconium (IV) acetylacetonate, titanium (IV) butoxide or scandium triflate, the synthesis being carried out in bulk or in a solvent.

The course of the reaction is controlled both by the amount of functionalized carbonate monomer added and by the process conditions, by melt or solvent solution synthesis

Organic, selected from the group consisting of cyclic oxides, preferably tetrahydrofuran, aromatic hydrocarbons, preferably toluene, chlorobenzene, alkyl sulfoxides, preferably dimethyl sulfoxide, and ethers and esters at a temperature of -20 ° C to 130 ° C for a period of 5 s to 150 h , in the presence of a non-toxic transesterification-promoting catalyst, preferably selected from the group consisting of acetylacetonates, alkyls, halides, alkoxides and / or triflates of zirconium (IV), iron (III), titanium (IV), scandium (III), preferably zirconium (IV) acetylacetonate, iron (III) acetylacetonate or titanium (IV) butoxide or scandium triflate.

The obtained partially cross-linked copolymer ((pre) polymer - material with a degree of cross-linking, preferably in the range from 1% to 15%), is processed by solution techniques, preferably film casting, fiber spinning, and solvent-free techniques typical for thermoplastic processing, preferably extrusion , alloy pouring and injection.

According to the invention, it has surprisingly been possible to give the designed shape to biodegradable polymeric materials with a high degree of cross-linking, of the duroplast type, which cannot be processed by methods used in the processing of thermoplastics, already at the stage of synthesis of this material. For this reason, the synthesis of the polymer is carried out in an appropriately constructed form, reflecting the shape of the target object.

Preferably, according to the invention, monomers which are cyclic lactones and / or lactides and / or cyclic carbonates are mixed with each other in a mixer with the addition of a cross-linking agent which is an ester-functionalized cyclic six-membered carbonate, particularly preferably 5-methyl-2-oxo-1,3. -dioxane-5-carboxylate (2-tert-butoxy-2-oxoethyl), in an amount of 3 to 60 mol% and optionally polymeric polyalcohols with a number of hydroxyl groups in the molecule greater than 2, preferably obtained by ROP carbonate polymerization reaction trimethylene or / and ε-caprolactone in the presence of polyhydric alcohols, preferably pentaerythritol and / or glycerin and / or mannitol. The mixture is melted and the temperature is maintained between 50 ° C and 130 ° C. A conventional ring opening catalyst for this type of monomers is then introduced into the resulting alloy, preferably zirconium (IV) acetylacetonate or zinc (II) acetylacetonate monohydrate, maintaining the temperature in the range of 50 ° C to 130 ° C. The pre (co) polymerization reaction is carried out in a mixer for a period of 5 s to 30 minutes, and then the prepolymer obtained in this way is poured into a prepared heated mold at a temperature of 80 ° to 130 ° C, where the actual polymerization stage takes place. During the ongoing (co) polymerization process, the mold temperature should be maintained from 80 ° C to 130 ° C throughout the appropriately selected reaction time, so that the conversion of all the reactants is close to 100%. After this time, the mold is gradually cooled down to room temperature, after which it can be opened and the finished solid object, with a previously planned shape consistent with the mold representation, made of bioresorbable polymer material, can be taken out.

In the method according to the invention, the polymerization is preferably carried out in a sealed form that resembles the target shape, allowing to obtain ready-made medical implants, both with planned shape and sterility, enabling their biomedical use without additional operations, provided that appropriate sterility conditions are maintained during the product deformation and packaging operations, and carrying out the polymerization above 110 ° C for more than 1 hour, preferably at 120 ° C for more than 18 hours.

A significant advantage of the method of obtaining finished products for biomedical applications according to the invention, in contrast to the currently used technological lines, is the possibility of skipping the sterilization operation, thanks to which the material before implantation does not degrade, which is accompanied by sterilization, causing a decrease in the mechanical strength of the product during exposure to sterilizing agents.

The rate of bioabsorption and the mechanical properties of the implants obtained by the method according to the invention can be adjusted to correlate it with the rate of tissue regeneration by selecting the optimal composition of the reaction mixture, including the amount of cross-linking agent and / or polyalcohol and the reaction conditions of the type of initiator and / or catalyst and reaction temperatures. All these factors determine the composition, structure and degree of cross-linking of the bioresorbable polymeric material chain formed in the polymerization process, preferably aliphatic polyesters-co-carbonates such as poly (L-lactide-co-ε-caprolactone-co-carbonate (s)) or poly (D, L-lactide-co-glycolide-co-carbonate (s)) or poly (L-lactide-co-glycolide-co-e-caprolactone-co-carbonate (s)) or poly (butyl succinate) L-lactide-co-carbonate (s) or poly (L-lactide-co-carbonate (s)).

The following examples illustrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention.

PL 235 484 B1

P r z k ł a d I

In order to obtain a biocompatible and biodegradable terpolymer with increased mechanical properties, a mixture of dry oxacyclic compounds consisting of 10.8 g of L-lactide (75% mol.), 2.3 g of glycolide (20% mol.) And 1.4 g of (2-tert-butoxy-2-oxoethyl) 5-methyl-2-oxo-1,3-dioxane-5-carboxylate (5 mol%). Then 0.06 g of zirconium (IV) acetylacetonate was added, mixed, and transferred to a heated mold while still maintaining anhydrous condition, which was sealed after filling. The mold was thermostated for 36 h at 120 ° C and then 72 h at 110 ° C. After cooling the mold to room temperature, the product was obtained in the form of a transparent yellowish rod with a diameter of 10 mm. Monomer conversion was 99.3% determined by 1H NMR.

The conventional copolymerization of L-lactide with glycolide was carried out under identical conditions to obtain a PLAGA copolymer rod having a composition of 83 mol%. lactidyl and 17 mol% glycolide which is the reference material.

The obtained terpolymer was only partially soluble in chloroform, and the resulting solution was opalescent, unlike the reference material which completely dissolved in chloroform. The glass transition temperature of the obtained terpolymer (Tg), determined by the differential scanning calorimetry method, was Tg = 50 ° C (Tg of the reference material = 55 ° C), at the same time no melting point was demonstrated for both materials. The three-point bending tests showed: maximum bending stress σ = 37 MPa; stiffness modulus E = 1783 MPa; while the reference material was characterized by significantly lower bending strength (σ = 20 MPa; E = 1259 MPa, respectively).

P r z x l a d II

In order to obtain an implant used in surgery to bond bone lesions, a biocompatible and biodegradable terpolymer with enhanced mechanical properties, initially an oligomer was obtained by ring-opening polymerization of 20 g of cyclic trimethylene carbonate, catalyzed with 0.03 g of zinc (II) acetylacetonate monohydrate in the presence of 0.25 g of tetra (hydroxymethyl) methane as an initiator. The polymerization was carried out in the melt at 130 ° C for 4 hours. The obtained oligomer had a number of hydroxyl end groups of about 4 per molecule and contained 6 wt. gel fraction, insoluble in chloroform. The average molar mass of the oligomer, determined by observing the chain end groups by NMR, was approximately 3100 g / mol.

Next, 14 g of L-lactide (70% by weight), 2 g of glycolide (10% by weight) and 4 g of the previously obtained oligomer (20% by weight) were introduced into a heated 50 ml reactor, equipped with a stirrer and an inert gas supply, under anhydrous conditions. wt.%). The formed mixture was heated under a blanket of dry inert gas to a temperature of 130 ° C with vigorous stirring. While a homogeneous melt was obtained, 0.07 g of zirconium (IV) acetylacetonate was added to the contents of the reactor with continued heating and stirring. After 15 minutes, the contents of the reactor were poured into a previously prepared mold, heated to 150 ° C, while maintaining anhydrous conditions, which was tightly closed after filling. The mold was thermostated for 80 h at 120 ° C. Monomer conversion was 98.5% determined by 1 H NMR. After cooling the mold to room temperature, a product was obtained in the form of a transparent osteosynthetic screw with a diameter of 5 mm, a thread height of 2 mm and a thread pitch of 4 mm. The tensile strength of the obtained bolt at break was 59 MPa and the Young's modulus was 1850 MPa.

P r x l a d III

In order to obtain a biocompatible and biodegradable terpolymer with enhanced mechanical properties, under anhydrous conditions, 30 cm ^{3 of} anhydrous THF were placed in a reactor equipped with an argon supply, a stirrer and a reflux condenser, and then 10.8 g of L-lactide were gradually added with constant stirring. (75 mole%), 2.3 g glycolide (20 mole%) and 1.4 g 5-methyl-2-oxo-1,3-dioxane-5-carboxylate (2-tert-butoxy-2-oxoethyl ) (5 mol%). The content of the reactor was heated to a temperature of 45 ° C, after dissolution of the monomers, 0.06 g of zirconium (IV) acetylacetonate was added. The reaction was carried out at about 50 * 55 ° under an argon blanket for the next 48 h with constant stirring. At this time, the reaction product was precipitated from cold methanol and dried in vacuo to a constant weight. Monomer conversion was approximately 80% as determined by 1H NMR. The obtained was partially insoluble in chloroform, containing about 20 wt. gel fraction of terpolymer. This product could be processed by pressing at 180 ° C. The three-point bending tests carried out on beams made of the obtained material showed: maximum bending stress σ = 30 MPa; stiffness modulus E = 2200 MPa.

Claims (6)

1. A method of producing bioresorbable polymeric materials with a controlled degree of cross-linking for medical applications in the process of (co) polymerization of lactide (s) and / or glycolide and / or β-caprolactone and / or other lactones and / or cyclic six-membered carbonates, characterized in that a polymer material consisting of a copolymer of lactide (s), glycolide, β-caprolactone and / or cyclic six-membered carbonates, is obtained by copolymerization of the abovementioned monomers with the addition of a cross-linking agent, which is an ester-functionalized cyclic six-membered carbonate with the general formula from or branched alkyl group with a carbon number of 1 to 8, halogenated alkyl, 2-tert-butoxy-2-oxoethyl group, preferably 5-methyl-2-oxo-1,3-dioxane-5-carboxylate (2-tert- butoxy-2-oxoethyl), wherein the copolymerization is carried out in bulk or in a solvent in the presence of an initiator and / or a catalyst selected from the group consisting of acetyls zirconium (IV), iron (III), titanium (IV) and / or scandium (III) tonics, alkyls, halides, alcoholates and / or triflates, 2. The method according to p. The method of claim 1, characterized in that the copolymerization of the corresponding monomers with the ester-functionalized six-membered carbonate is carried out in the presence of known transesterification-promoting coordination catalysts commonly used in the polymerization of lactides and lactones, preferably titanium (IV) butoxide or zirconium (IV) acetylacetonate. 3. The method according to p. The method of claim 1, wherein the ester-functionalized six-membered carbonate is used in an amount of 3 to 95 mole%, preferably 3 to 10 mole%, for melt processable materials and up to 60 mole% for in-mold polymerized materials. 4. The method according to p. The process of claim 1, wherein the (co) polymerization is performed in the melt. 5. The method according to p. A process as claimed in claim 1, characterized in that the (co) polymerization is carried out in an organic solvent selected from the group consisting of ethers, preferably tetrahydrofuran, aromatic hydrocarbons, preferably toluene, chlorobenzene, alkyl sulfoxides, preferably dimethyl sulfoxide, and esters. 6. The method according to p. The process of claim 1, characterized in that the (co) polymerization is carried out at a temperature of -20 to 130 ° C for a period of 5 s to 150 h, preferably at a temperature of 50 ° C to 120 ° C.