CN112961333A - Bioabsorbable copolymer, preparation method thereof and medical instrument - Google Patents

The invention discloses a bioabsorbable copolymer, a preparation method thereof and a medical apparatus, and relates to the technical field of bioabsorbable medical materials. The bioabsorbable copolymer is copolymerized from a monomer A and a monomer B, wherein the monomer A comprises lactide and the monomer B comprises at least one of epsilon-caprolactone and trimethylene carbonate. The bioabsorbable copolymer provided by the invention is used for medical devices such as suture threads and the like, has high toughness and can maintain high mechanical strength.

Bioabsorbable copolymer, preparation method thereof and medical instrument

Technical Field

The invention relates to the technical field of bioabsorbable medical materials, in particular to a bioabsorbable copolymer, a preparation method thereof and a medical apparatus.

Background

Bioabsorbable materials have been used in medical, environmental, and other fields for a long time. Biodegradable medical materials have been vigorously developed especially in the field of medical and health. The absorbable material, i.e. biodegradable material, is a synthetic organic polymer or natural polymer, which undergoes hydrolysis and oxidation in vivo to obtain CO as the final product₂And H₂O, is discharged out of the body through the respiratory system or the urinary system, is not accumulated in the body, has almost no toxic effect, does not need to be taken out again by operation, and has different decomposition and absorption cycles according to different molecular structures and different environmental conditions of the material.

A very important aspect of any bioabsorbable medical device is the need to have good flexibility and to maintain high mechanical strength, so as to facilitate the surgical operation and to fulfil its function as a medical device. However, the toughness and strength of the existing bioabsorbable materials are poor, so that the application of the existing bioabsorbable materials is limited.

Disclosure of Invention

The invention mainly aims to provide a bioabsorbable copolymer and a preparation method thereof, and aims to solve the problem that the existing bioabsorbable material is poor in toughness and strength.

To achieve the above object, the present invention proposes a bioabsorbable copolymer, which is copolymerized from a monomer a and a monomer B, wherein the monomer a includes lactide and the monomer B includes at least one of epsilon-caprolactone and trimethylene carbonate.

Optionally, the lactide comprises at least one of L-lactide and derivatives thereof and D-lactide and derivatives thereof.

Optionally, the bioabsorbable copolymer has a crystallinity of no less than 20%.

Optionally, in the bioabsorbable copolymer, the molar content of the unit formed by the monomer a is 60% to 99%, and the molar content of the unit formed by the monomer B is 1% to 40%.

Optionally, in the bioabsorbable copolymer, the molar content of the units formed from monomer a is 75% to 90% and the molar content of the units formed from monomer B is 10% to 25%.

Optionally, monomer B comprises epsilon-caprolactone and trimethylene carbonate, wherein the molar content of units formed from the epsilon-caprolactone in the bioabsorbable copolymer is from 9% to 24%.

Optionally, the bioresorbable copolymer has an intrinsic viscosity of no less than 1.1 dL/g.

The invention also provides a preparation method of the bioabsorbable copolymer, which comprises the following steps:

and carrying out ring-opening polymerization on the monomer A and the monomer B under the action of an initiator and a catalyst to obtain the bioabsorbable copolymer.

In addition, the invention also provides a medical appliance, wherein the material of at least part of the structure of the medical appliance comprises the bioabsorbable copolymer.

Optionally, the medical device is a suture, drug-eluting carrier, tissue fixation device, nail, clip, mesh fixation device, anastomosis device, bone anchor, bone screw, bone plate, prosthesis, support structure, tissue reinforcement structure, tissue ligation device, matrix, patch, mesh, tissue engineering scaffold, prosthetic ligament, tendon, vascular graft, drug delivery device, or stent.

The bioabsorbable copolymer provided by the invention is formed by copolymerizing a monomer A and a monomer B, wherein the monomer A comprises lactide, and the monomer B comprises at least one of epsilon-caprolactone and trimethylene carbonate. The monomer A can be connected with the monomer B or self, and the monomer B can also be connected with self to finally form a semi-crystalline block binary copolymer or semi-crystalline block ternary copolymer, namely a bio-absorbable copolymer, so that the formed bio-absorbable copolymer is used for medical devices such as sutures and the like, has high toughness and can maintain high mechanical strength.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

The toughness and the strength of the existing bioabsorbable material are poor, so that the application of the existing bioabsorbable material to partial medical devices is limited.

The bioabsorbable copolymer is copolymerized from a monomer A and a monomer B, wherein the monomer A comprises lactide and the monomer B comprises at least one of epsilon-caprolactone and trimethylene carbonate. That is, monomer B may be epsilon-caprolactone, trimethylene carbonate, or both epsilon-caprolactone and trimethylene carbonate.

In the technical scheme of the invention, the monomer A can be connected with the monomer B or the monomer B, and the monomer B can also be connected with the monomer B to finally form a semi-crystalline block binary copolymer or semi-crystalline block ternary copolymer, namely a bioabsorbable copolymer, so that the formed bioabsorbable copolymer is used for medical devices such as sutures and the like, has high toughness and can maintain high mechanical strength.

It is to be understood that the bioabsorbable copolymer provided by the present invention can be three types of absorbable copolymer (I), (II) or (III), wherein bioabsorbable copolymer (I) comprises lactide and epsilon-caprolactone, bioabsorbable copolymer (II) comprises lactide and trimethylene carbonate, and bioabsorbable copolymer (III) comprises lactide, epsilon-caprolactone and trimethylene carbonate.

Wherein the lactide comprises at least one of L-lactide and derivatives thereof and D-lactide and derivatives thereof. That is, the lactide may be L-lactide and its derivatives, may be D-lactide and its derivatives, or may be both L-lactide and its derivatives and D-lactide and its derivatives. L-lactide is readily absorbed by the human body, and therefore, preferably, the lactide is L-lactide.

Further, in this embodiment, the bioabsorbable copolymer has a crystallinity of not less than 20%, and at this time, the melting temperature of the bioabsorbable copolymer is at least 150 ℃, so that the bioabsorbable copolymer can achieve a strength retention for a long time.

The present invention does not limit the molar content of each component of the absorbable copolymer, and in one embodiment, the molar content of the unit formed by the monomer A is 60 to 99%, and the molar content of the unit formed by the monomer B is 1 to 40%, and at this time, the suture made of the bioabsorbable copolymer is sufficiently soft and the mechanical strength is maintained for a long time. Preferably, in the bioabsorbable copolymer, the molar content of the unit formed by the monomer A is 75 to 90 percent, and the molar content of the unit formed by the monomer B is 10 to 25 percent. More preferably, in the bioabsorbable copolymer, the molar content of the unit formed by the monomer A is 80 to 85 percent, and the molar content of the unit formed by the monomer B is 15 to 20 percent.

Furthermore, the monomer B is preferably epsilon-caprolactone and trimethylene carbonate, and the molar content of a unit formed by the epsilon-caprolactone is 9-24%, so that the performance of the bioabsorbable copolymer is better.

Intrinsic viscosity refers to reduced viscosity when the concentration of a polymer solution approaches zero, i.e., represents the contribution of a single molecule to the viscosity of the solution, and is a viscosity reflecting the characteristics of a polymer, and its value does not vary with the concentration. In this embodiment, the intrinsic viscosity of the bioabsorbable copolymer is not less than 1.1dL/g, and the intrinsic viscosity and the limit on the crystallinity together serve to maintain the long strength of the bioabsorbable copolymer as a medical device.

The invention also provides a preparation method of the bioabsorbable copolymer, which comprises the following steps:

s10, carrying out ring-opening polymerization on the monomer A and the monomer B under the action of an initiator and a catalyst to obtain the bioabsorbable copolymer.

Wherein the initiator comprises any one of 1, 3-propylene glycol and decanol, and the catalyst comprises stannous octoate toluene. Furthermore, the present invention is not limited to the order of addition of the monomer a and the monomer B, and may be prepared by first preparing poly-epsilon-caprolactone/trimethylene carbonate (i.e., adding the monomer B first) and then reacting it with L-lactide and its derivatives; epsilon-caprolactone, trimethylene carbonate, L-lactide and derivatives thereof may also be added simultaneously to react so long as the bioabsorbable copolymer is finally obtained.

Furthermore, the invention also provides a medical appliance, wherein the material of at least part of the structure of the medical appliance comprises the bioabsorbable copolymer.

Wherein the medical device is a suture, drug-eluting carrier, tissue fixation device, nail, clip, mesh fixation device, anastomosis device, bone anchor, bone screw, bone plate, prosthesis, support structure, tissue reinforcement structure, tissue ligation device, matrix, patch, mesh, tissue engineering scaffold, prosthetic ligament, tendon, vascular graft, drug delivery device, or stent.

Specifically, the bioabsorbable copolymer can be made into a fabric by using a conventional method, such as melt extrusion, melt blowing, and the like, and can also be injection molded into the above other medical devices in a mold. The suture comprises any one of monofilament and multifilament yarns, and the suture has a modulus of elasticity greater than about 100000psi, a tensile strength greater than about 40000psi, and an elongation less than about 80%. The suture produced by the present invention is absorbable in less than three years of human body and retains at least 50% of its initial strength at 6 weeks after implantation.

Furthermore, the bioabsorbable copolymer can also be made into a fabric by electrospinning techniques. The drug sustained-release carrier comprises any one of microcapsules and microspheres. The vascular graft is made entirely of the multifilament yarn or a combination of existing multifilaments and monofilaments or a combination with other more absorbable multifilament or monofilament yarns.

The medical device prepared by the invention can be absorbed after being implanted into a body, the mechanical strength can be kept for a long time, and in addition, the limit formed by the bioabsorbable copolymer has good flexibility and tensile mechanical strength, and has good formability and dimensional stability of molding equipment.

The technical solutions of the present invention are further described in detail with reference to the following specific examples, which should be understood as merely illustrative and not limitative.

EXAMPLE 150/50 preparation of Poly epsilon-caprolactone/trimethylene carbonate

122.9 g (1.204mol) of trimethylene carbonate was added to a 1 liter 316L stainless steel belt heating oil jacketed reactor equipped with a stirring device, the reactor was maintained at high vacuum for 2 hours at room temperature, then inert gas was charged, and the temperature inside the reactor was heated to 100 ℃ using a high temperature oil bath. After the trimethylene carbonate had completely melted, 137.5 g (1.204mol) of ε -caprolactone and 1.3 g (0.016mol) of 1, 3-propanediol were added, followed by 1.72 mL (3.44X 10) of propylene glycol with stirring^-4mol) of 0.2M stannous octoate in toluene, finally raising the temperature to 180 ℃, and reacting for 1.5 hours at 180 ℃ to obtain 50/50 poly-epsilon-caprolactone/trimethylene carbonate.

The molecular weight was determined by gel permeation chromatography using methylene chloride as solvent. The results show that: mn 32000 and Mw 58000.

EXAMPLE 280/20 preparation of Poly epsilon-caprolactone/trimethylene carbonate

55.2 g (0.538mol) of trimethylene carbonate was added to the reactor, the reactor was maintained under high vacuum at room temperature for 2 hours, then charged with inert gas, and the temperature inside the reactor was heated to 100 ℃ using a high temperature oil bath. After the trimethylene carbonate had completely melted, 245.3 g (2.15mol) of ε -caprolactone and 1.3 ml (1.792X 10) were added^-2mol)1, 3-propanediol and 1.92 ml (3.84X 10)^-4mol) of stannous octoate in toluene, finally the temperature was raised to 180 ℃ and the reaction was carried out at 180 ℃ for 1 hour to give 80/20 poly-epsilon-caprolactone/trimethylene carbonate.

The molecular weight was determined by gel permeation chromatography using methylene chloride as solvent. The results show that: mn 46000 and Mw 75000.

EXAMPLE 3 preparation of bioabsorbable copolymer

253 g (1.754mol) of L-lactide and 47.5 g (0.438mol) of 50/50 epsilon-caprolactone/trimethylene carbonate prepared in example 1 were added to a reactor, the reactor was maintained under high vacuum at room temperature for 1 hour, then charged with an inert gas, a high temperature oil bath was used, the temperature in the reactor was heated to 40 ℃ and maintained under vacuum for 30 minutes, an inert gas was charged, the oil bath temperature was then increased to 140 ℃ and stirred at 120rpm for 30 minutes until the raw materials were completely melted, and the oil bath temperature was lowered to 110 ℃. Then 0.235ml (4.693X 10) was added to the kettle while stirring^-5mol) of 0.2M stannous octoate in toluene, finally the temperature was raised to 140 ℃ and the stirring rate was reduced to 50rpm, after which the stirring was stopped after 2 hours and kept at 140 ℃ for another 36 hours, giving 20/80 (50/50. epsilon. -caprolactone/trimethylene carbonate)/L-lactide block copolymer, i.e. a bioabsorbable copolymer.

The bioabsorbable copolymer had an intrinsic viscosity of 1.4dl/g as measured by chloroform as a solvent, and a melting temperature and a heat of fusion of 187.6 ℃ and 50J/g, respectively, as measured by differential scanning calorimetry.

EXAMPLE 4 preparation of bioabsorbable copolymer

13 g (0.111 mol.) of ε -caprolactone, 240.1 g (1.665 mol.) of L-lactide and 48.0 g (0.444 mol.) of 50/50 ε -caprolactone/trimethylene carbonate from example 1 were added to a reactor, the reactor was maintained under high vacuum at room temperature for 1 hour, then charged with an inert gas, the temperature in the reactor was heated to 40 ℃ using a high temperature oil bath and maintained under vacuum for 30 minutes, then charged with an inert gas, the oil bath temperature was increased to 140 ℃ and stirred at 120rpm for 30 minutes until the raw materials were completely melted, the oil bath temperature was reduced to 110 ℃, then 0.238 ml (4.76X 10X^-5mol) of 0.2M stannous octoate in toluene, finally increasing the temperature to 140 ℃ and reducing the stirring rate to about 50rpm, stopping the stirring after about 2.5 hours, and keeping at 140 ℃ for 36 hours to obtain 20/80(50/50 epsilon-caprolactone/trimethylene carbonate)/(92/8L-lactide/epsilon-caprolactone) block copolymer, i.e., bioabsorbable copolymer.

The bioabsorbable copolymer had an intrinsic viscosity of 1.25dl/g as measured by chloroform as a solvent, and a melting temperature and a heat of fusion of 175.2 ℃ and 59.5J/g as measured by differential scanning calorimetry, respectively.

EXAMPLE 5 preparation of bioabsorbable copolymer

18.3 g (0.156 mol.) of ε -caprolactone, 258.6 g (1.793 mol.) of L-lactide and 25.1 g (0.216 mol.) of 80/20 ε -caprolactone/trimethylene carbonate from example 2 were added to a reactor, the reactor was maintained under high vacuum at room temperature for 1 hour, then inert gas was charged, the temperature in the reactor was heated to 40 ℃ using a high temperature oil bath and maintained under vacuum for 30 minutes, then inert gas was charged, the oil bath temperature was raised to 140 ℃ and stirred at 120rpm for 30 minutes until the raw materials were completely melted, the oil bath temperature was lowered to 110 ℃, and finally 0.385 ml (7.71X 10 ml) of oil (7.71X 10 ml) was added to the kettle while stirring^-5mol) of a 0.2M toluene solution of stannous octoate, increasing the temperature to 140 ℃ and decreasing the stirring rate to about 40rpm, stopping the stirring after about 2 hours, and maintaining at 140 ℃ for 36 hours to obtain 10/90(80/20 epsilon-caprolactone/trimethylene carbonate)/(92/8L-lactide/epsilon-caprolactone) block copolymer, i.e., a bioabsorbable copolymer.

The bioabsorbable copolymer had an intrinsic viscosity of 2.46dl/g as measured by chloroform as a solvent, and a melting temperature and a heat of fusion of 176.2 ℃ and 42.7J/g as measured by differential scanning calorimetry, respectively.

EXAMPLE 6 preparation of bioabsorbable copolymer

16.8 g (0.14672mol) of poly-epsilon-caprolactone, 3.0 g (0.02934mol) of trimethylene carbonate and 80.3 g (0.55754mol) of L-lactide are added into a reactor, the reactor is maintained at room temperature under high vacuum for 1 hour, then inert gas is filled, high-temperature oil bath is used, the temperature in the reactor is heated to 40 ℃ and is kept under vacuum for 30 minutes, finally, inert gas is filled, the oil bath temperature is increased to 140 ℃, stirring is stopped after 5 hours at 45rpm, and then stirring is kept at 140 ℃ for 72 hours, so that 20/80 poly-epsilon-caprolactone/(95/5L-lactide/trimethylene carbonate) block copolymer, namely the bioabsorbable copolymer, is obtained.

The bioabsorbable copolymer had an intrinsic viscosity of 1.13dl/g as measured by chloroform as a solvent, and a melting temperature and a heat of fusion of 172.6 ℃ and 58.6J/g as measured by differential scanning calorimetry, respectively.

EXAMPLE 7 preparation of bioabsorbable copolymer

Adding 29.3 g (0.2844mol) of trimethylene carbonate and 471 g (3.2706mol) of L-lactide into a reactor, maintaining the reactor at room temperature under high vacuum for 1 hour, then charging inert gas, using high-temperature oil bath, heating the temperature in the reactor to 40 ℃, keeping the temperature under vacuum for 30 minutes, finally charging inert gas, raising the temperature of the oil bath to 110 ℃, stirring at 120rpm for 1 hour until the raw materials are completely melted, then adding 0.452 ml (2.37X 10 mol) of L-lactide into the kettle while stirring^-3mol) decanol and 0.889 ml (1.7775X 10)^-4mol) of 0.2M stannous octoate in toluene, increasing the temperature to 140 ℃, reducing the stirring speed to 40rpm, stopping stirring after 45 minutes, and keeping at 140 ℃ for 48 hours to obtain 92/8L-lactide/trimethylene carbonate polymer, namely, the bioabsorbable copolymer.

The bioabsorbable copolymer had an intrinsic viscosity of 3.53dl/g as measured by chloroform as a solvent, and a melting temperature and a heat of fusion of 182.7 ℃ and 59J/g as measured by differential scanning calorimetry, respectively.

EXAMPLE 8 preparation of bioabsorbable copolymer

Adding 3.542 g (0.0344mol) of trimethylene carbonate and 492 g (3.41193mol) of L-lactide into a reactor, maintaining the reactor at room temperature under high vacuum for 1 hour, then charging inert gas, using high-temperature oil bath, heating the temperature in the reactor to 40 ℃, maintaining the temperature under vacuum for 30 minutes, finally charging inert gas, increasing the temperature of the oil bath to 110 ℃, stirring for 1 hour at 120rpm until the raw materials are completely melted, then adding decanol and 0.2M stannous octoate toluene solution into the reactor while stirring, increasing the temperature to 140 ℃, reducing the stirring speed to 40rpm, stopping stirring after 45 minutes, and maintaining the temperature at 140 ℃ for 48 hours to obtain 99/1L-lactide/trimethylene carbonate polymer, namely the bioabsorbable copolymer.

The bioabsorbable copolymer had an intrinsic viscosity of 4.26dl/g as measured by chloroform as a solvent, and a melting temperature and a heat of fusion of 187.8 ℃ and 62J/g, respectively, as measured by differential scanning calorimetry.

EXAMPLE 9 preparation of bioabsorbable copolymer

Adding 176.3 g (1.507mol) of epsilon-caprolactone and 326 g (2.261mol) of L-lactide into a reactor, maintaining the reactor at room temperature under high vacuum for 1 hour, then filling inert gas, using a high-temperature oil bath, heating the temperature in the reactor to 40 ℃, keeping the temperature under vacuum for 30 minutes, finally filling the inert gas, raising the temperature of the oil bath to 110 ℃, stirring for 1 hour at 120rpm until the raw materials are completely melted, then adding decanol and 0.2M stannous octoate toluene solution into the reactor while stirring, raising the temperature to 140 ℃, reducing the stirring speed to 40rpm, stopping stirring after 45 minutes, and keeping the temperature at 140 ℃ for 48 hours to obtain 60/40L-lactide/trimethylene carbonate polymer, namely the bioabsorbable copolymer.

The bioabsorbable copolymer had an intrinsic viscosity of 2.13dl/g as measured by chloroform as a solvent, and a melting temperature and a heat of fusion of 165.5 ℃ and 48J/g as measured by differential scanning calorimetry, respectively.

Bioabsorbable copolymers prepared in examples 3 to 5 above were vacuum dried at 40 ℃ for 8 hours or more, then vacuum dried at 80 ℃ for at least 4 hours, monofilament yarns were extruded using a single screw, the monofilament yarns were cultured in a phosphate buffer solution at 37 ℃ and pH 7.4, and their properties were tested, and the results are shown in Table 1:

TABLE 1 Performance test

As can be seen from Table 1, the monofilament yarns obtained in examples 3 to 5 all had a melting temperature higher than 150 ℃, an elongation lower than 80%, and a mechanical strength of at least 50% of the initial strength after implantation for 6 weeks. Therefore, the bioabsorbable polymer prepared by the invention has high toughness and high dimensional stability, and can keep mechanical strength for a long time in an implant.

The above is only a preferred embodiment of the present invention, and it is not intended to limit the scope of the invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall be included in the scope of the present invention.