CN112516390B

CN112516390B - Degradable ureter stent

Info

Publication number: CN112516390B
Application number: CN202011096450.7A
Authority: CN
Inventors: 熊成东; 陈和春; 陈栋梁; 王昕�; 陈龙; 肖建平; 包一红
Original assignee: Zhejiang Zhongzai Medical Technology Co ltd
Current assignee: Zhejiang Zhongzai Medical Technology Co ltd
Priority date: 2020-10-14
Filing date: 2020-10-14
Publication date: 2022-08-05
Anticipated expiration: 2040-10-14
Also published as: CN112516390A

Abstract

The invention provides a degradable ureteral stent which is of a round tubular structure, the adopted material is a composite material formed by two elastomers with different degradation speeds, the material with the slower degradation speed is an L-lactide/epsilon-caprolactone copolymer, and the material with the faster degradation speed is a glycolide/epsilon-caprolactone copolymer. The degradable ureteral stent has the advantages of higher tensile strength, adjustable degradation time, more stable size after molding, excellent resilience and the like, can meet the requirements of degradation speed required by different clinical indications, and can also achieve better mechanical properties. The composite material can also be mixed with a medical developer, a processing aid and the like, and the ureter stent is obtained by extrusion molding.

Description

Degradable ureter stent

Technical Field

The invention belongs to the field of biomedical materials, and particularly relates to a degradable ureteral stent.

Background

The ureter bracket has wide application in urinary surgery, is suitable for the treatment processes of upper urinary tract operation, stone breaking by a stone breaker, expansion of ureter stenosis and the like, and can play important roles in draining urine and preventing ureter stenosis after being implanted into a ureter. At present, ureteral stents used in clinical application are tubular structures, have elasticity and certain strength, and are curled into a coil shape at two ends or one end (double pigtail catheters, or D-J tubes; single J tubes). When in operation, the instrument is implanted into a ureter which connects the kidney and the bladder, the upper end of the instrument is hung on the renal pelvis to be fixed, and the lower end of the instrument enters the bladder to be fixed. Usually, the time for placing in the body as a ureteral stent for draining urine varies from 2 to 8 weeks depending on the indication, and then the patient goes to a hospital and is pulled out of the body through the cystoscope into the urethra. Too long retention time may cause calculi and more complications, and too short retention time may lead to unsatisfactory drainage or stone removal effect.

The existing ureteral stents used in clinic are all made of elastic polyurethane materials or silicon rubber materials, and are not degradable. Such non-degradable ureteral stents, when placed into a patient and after they have completed their drainage function, must be removed by invasive procedures, i.e., by cystoscopy, and can cause painful patients and complications such as infection. Therefore, research and development of degradable ureteral stents is imminent.

Foreign literature reports (Laaksovirta, S Laurila M.et al.J.urol, 167:1527,2002) that ureteral stents are manufactured by using degradable lactide/glycolide copolymers (PLGA) as raw materials. However, PLGA materials are relatively hard, have a glass transition temperature above human body temperature, are not flexible, have an elongation at break of less than 20%, and may embed or puncture ureteral lining tissue with degraded debris.

Lumiaho, J et al (J. Endouronl.1999, 13, 107-112) studied the placement of polylactic acid-made ureteral stents into the ureters of swine and showed good drainage. However, polylactic acid materials are hard, have a glass transition temperature above the temperature of a human body, have no flexibility, have an elongation at break of less than 20 percent, and are likely to cause blockage of the ureter by degraded fragments, which are hard and embedded into the endoureteral tissue.

Chinese patent CN 103041454A discloses a degradable ureteral stent composite material, which uses a L-lactide/epsilon-caprolactone binary copolymer (PLC copolymer). The PLC copolymer degrades slowly, and the patent also uses crosslinked polyvinylpyrrolidone (PVPP), and the degradation rate of the ureteral stent can be improved by utilizing the very good water swelling property of the PVPP to cause very high pressure inside the ureteral stent through water absorption. However, the addition of PVPP has problems such as a decrease in strength of the material.

In the L-lactide/epsilon-caprolactone bipolymer (PLC copolymer), epsilon-caprolactone units can provide flexibility, and L-lactide units can provide mechanical strength. When the mole content of the epsilon-caprolactone in the copolymer is lower than 25 percent, the copolymer has an ordered structure, obvious crystallization tendency and poor resilience; when the molar content is more than 50%, the copolymer is a completely disordered structure, the mechanical strength is obviously reduced, and the copolymer is softer and has poor resilience. The copolymer is an elastomer having a certain strength only when the epsilon-caprolactone is present in the copolymer in a molar amount in the range of about 25% to about 50%. Although L-lactide and epsilon-caprolactone are chain unit structures with slow degradation, the elastomer has slow degradation speed and is not suitable to be used as a material for degrading the ureteral stent alone; in addition, since the ordered structure or the crystallization tendency of the L-lactide segment is greatly disturbed by the copolymerization of the elastomer, there are problems that the mechanical strength is still insufficient and the size of the product after extrusion molding is unstable.

U.S. patent 5085629 discloses ureteral stents made from degradable terpolymers whose monomer components are L-lactide, glycolide, and epsilon-caprolactone, which is also an elastomer at room temperature when the epsilon-caprolactone content reaches a certain ratio. Due to the fact that the glycolide unit can improve the degradation speed, the glycolide content can be adjusted to enable the terpolymer to reach the required degradation time, but the introduction of glycolide can further disturb the ordered structure or the crystallization tendency of an L-lactide chain segment, so that the mechanical strength of the L-lactide/glycolide/epsilon-caprolactone terpolymer is reduced, and the size of a finished piece after extrusion molding is also unstable.

The glycolide/epsilon-caprolactone binary random copolymer is prepared by randomly copolymerizing glycolide and epsilon-caprolactone, and is a degradable high-molecular elastomer with better strength. In the copolymer, epsilon-caprolactone units can provide flexibility, and glycolide units can provide higher mechanical strength than L-lactide. When the content of epsilon-caprolactone in the copolymer is in the range of about 30 to 50 mol%, the copolymer is an elastomer with better strength, because the copolymer has a disordered structure to a certain extent, and the glycolide structural units still have a certain crystallization tendency, and the crystallization capability brings about the improvement of the mechanical properties of the material. Also for this reason, the elastomer has good dimensional stability. Nevertheless, glycolide is a chain building block that degrades rapidly, making the elastomer degrade too rapidly to be practical for the clinically required 2-8 week drainage time.

Therefore, the degradable ureteral stent obtained in the prior art cannot simultaneously take into consideration the controllability of degradation speed, mechanical strength and dimensional stability after molding.

Disclosure of Invention

In view of the defects of the prior art, the invention provides a degradable ureteral stent which is made of a composite material formed by two elastomers with different degradation speeds, has the advantages of random controllability of the degradation speed, better mechanical property, more stable size after molding, excellent rebound resilience and the like, can meet the requirements of the degradation speeds required by different clinical indications, and can also achieve better mechanical property.

The degradable ureter stent is made of a composite material formed by blending the following two degradable high polymer materials, and comprises the following components in percentage by weight:

1) l-lactide/epsilon-caprolactone copolymer: 20 to 95 percent

2) Glycolide/epsilon-caprolactone copolymer: 5 to 80 percent of

The invention is based on the unexpected discovery that in an elastic material L-lactide/epsilon-caprolactone copolymer (PLC) with slower degradation, an elastic material glycolide/epsilon-caprolactone copolymer (PGC) with faster degradation is blended in a certain proportion, so that the formed composite material (PLC/PGC) has very good compatibility, the tensile strength of the composite material is obviously higher than that of the PLC, and the composite material is more stable in size and not easy to deform after being formed. This is particularly important for degradable ureteral stents, and improves the mechanical properties and dimensional stability of the material, meaning that the drainage, support and fixation effects of the ureteral stent will be better, and the wall thickness of the tube can be reduced to reduce the total implantation amount and reduce the risk of ureteral lumen blockage.

The degradable ureter stent is in a hollow round tube shape by thermoplastic extrusion molding of materials, the outer diameter of the tube is 1.0-3.2 mm, and the inner diameter of the tube is 0.6-2.0 mm.

The degradable ureter stent is formed by secondary molding on the basis of a circular tube, wherein the two ends or one end of the degradable ureter stent is provided with a fixing structure for preventing sliding, the fixing structure at one end is fixed at the position of a renal pelvis, and the fixing structure at the other end can be fixed at the position of a bladder.

Preferably, the fixing structure of the degradable ureteral stent is in a curled shape, can be in a circular curled shape, and can also be in a semicircular shape or other curled shapes. The curly shape is formed by curling a round tube shape, and the middle part is hollow.

The degradable ureteral stent is characterized in that a plurality of penetrating drainage side holes are formed in the wall of the tubular stent on the basis of a circular tube, the number and the aperture of the drainage side holes can be set according to the actual drainage effect, the drainage side holes are equidistant or unequal, and the drainage side holes are circular or elliptical.

Preferably, the composite material comprises 30-80% of L-lactide/epsilon-caprolactone copolymer and 20-70% of glycolide/epsilon-caprolactone copolymer in percentage by weight. Within the weight ratio range, the composite material has better strength and elasticity, and the formed degradable ureteral stent has better performance.

The invention also discovers that the performance of the degradable ureteral stent prepared by the copolymer of the L-lactide and the epsilon-caprolactone in the PLC copolymer and the glycolide and the epsilon-caprolactone in the PGC copolymer can be ensured by adjusting the selected copolymerization ratio.

The degradable ureteral stent comprises 25-50% of epsilon-caprolactone and 50-75% of L-lactide in molar ratio. The molar ratio of the L-lactide to the epsilon-caprolactone is changed within the range, which is a main measure for ensuring that the strength and the hardness of the L-lactide/epsilon-caprolactone copolymer meet the clinical use requirements. The L-lactide content is too high, and the material is too hard; the L-lactide content is too low, the material is too soft, and the mechanical strength is too low.

The degradable ureteral stent comprises, by mole, 30-50% of epsilon-caprolactone and 50-70% of glycolide.

The degradable ureteral stent also comprises a radiopaque medical developer, and the radiopaque medical developer is used for facilitating observation of the position of the degradable ureteral stent in a body in vitro.

Preferably, the medical developing agent is barium sulfate, and the content of the barium sulfate is 15-30%.

The degradable ureter stent provided by the invention has the advantages that the intrinsic viscosity of the L-lactide/epsilon-caprolactone copolymer in chloroform at 30 ℃ is 0.8-4.0 dl/g. The greater the intrinsic viscosity, the greater the material molecular weight.

Preferably, the intrinsic viscosity of the L-lactide/epsilon-caprolactone copolymer in chloroform at 30 ℃ is 1.2-3.0 dl/g, and the degradable ureter stent has better strength within the range.

The degradable ureter stent provided by the invention has the advantages that the intrinsic viscosity of the glycolide/epsilon-caprolactone copolymer in hexafluoroisopropanol at 30 ℃ is 0.5-3.0 dl/g.

Preferably, the intrinsic viscosity of the glycolide/epsilon-caprolactone copolymer in hexafluoroisopropanol at 30 ℃ is 1.0-2.0 dl/g, and within the range, the degradation time of the degradable ureteral stent can be better regulated, and the strength of the degradable ureteral stent can be improved.

The degradable ureteral stent has the advantages that the tensile strength of the composite material is greater than 10MPa and exceeds the mechanical strength of silicon rubber, so that the mechanical property equivalent to that of polyurethane can be achieved; the elongation at break is more than 300 percent, and the rubber is soft and elastic; the Shore hardness A ranges from 40 to 100 and is equivalent to the hardness of the existing silicone rubber or polyurethane ureteral stent.

In the invention, the preparation method of the L-lactide/epsilon-caprolactone copolymer comprises the following steps: placing the dehydrated and purified epsilon-caprolactone monomer and the recrystallized and purified L-lactide monomer into a reactor, adding 0.01-0.05% of stannous octoate catalyst, and reacting for 12-48 hours at the reaction temperature of 140-160 ℃ under the protection of nitrogen to obtain the copolymer. Dissolving the copolymer in dichloromethane, precipitating with ethanol, and drying the precipitate in a vacuum drier for 48 hr to obtain L-lactide/epsilon-caprolactone copolymerAn elastomeric material. The molar ratio of the two monomers in the copolymer is determined by ¹ The intrinsic viscosity was determined by HNMR using an Ubbelohde viscometer at 37 ℃ in 0.1% chloroform.

In the invention, the preparation method of the glycolide/epsilon-caprolactone copolymer comprises the following steps: placing the dehydrated and purified epsilon-caprolactone monomer and glycolide monomer into a reactor, adding 0.01-0.05 wt% of stannous octoate catalyst, reacting at 160-200 ℃ under the protection of nitrogen for 12-24 hours, transferring the polymer out of the reactor, further crushing the polymer into particles smaller than 3mm, and placing the particles into a vacuum oven at 90 ℃ for vacuum drying for 50 hours to remove unreacted monomer, thus obtaining the glycolide/epsilon-caprolactone copolymer. The molar ratio of the two monomers in the copolymer is determined by ¹ HNMR determined the intrinsic viscosity using an Ubbelohde viscometer in hexafluoroisopropanol at 37 ℃ at a concentration of 0.1%.

The invention also provides a preparation method of the degradable ureteral stent. The composite material or the composite material blended with the medical developer is melted and extruded by a single screw extruder to form the circular tubular degradable ureter stent; wherein the plasticizing temperature of the material is 100-180 ℃; the temperature of the extruder head is 100-170 ℃. The method is simple to operate and easy for large-scale preparation of the degradable ureteral stent.

In order to better process and form, a processing aid for improving the melt fluidity of the ureteral stent material can be added into the formula of the ureteral stent material, and besides a common plasticizer, the invention discovers that the addition of the poly epsilon-caprolactone can not only reduce the melt processing temperature and improve the extrusion stability, but also does not influence the mechanical property and the degradation property of a finished product.

The degradable ureteral stent can also realize the regulation and control of the degradation time. In the composite material, the higher the glycolide/epsilon-caprolactone copolymer content is, the faster the composite material degradation speed is. That is, the degradation speed of the L-lactide/epsilon-caprolactone copolymer with slower degradation can be accurately regulated and controlled by blending the glycolide/epsilon-caprolactone copolymer with faster degradation, and the mechanical property and the dimensional stability after extrusion molding can be obviously improved, which cannot be achieved by using the L-lactide/epsilon-caprolactone copolymer and the glycolide/epsilon-caprolactone copolymer independently. Meanwhile, the ureteral stent is also found to be axially cracked and broken after being degraded, and the degradation mode is more favorable for the ureteral stent to be discharged out of the ureteral cavity

Compared with the L-lactide/epsilon-caprolactone copolymer which is used alone, the degradable ureter stent has more stable size after being formed, can not shrink and deform in an in-vivo environment, and ensures the firmness and stability of the stent in the in-vivo position.

Therefore, the invention adopts the L-lactide/epsilon-caprolactone copolymer and the glycolide/epsilon-caprolactone copolymer to blend, then the blend is extruded and molded into a tubular structure, and finally the scaffold with a double J or single J structure commonly used in clinic is obtained through post-treatment such as punching, bending and the like, thereby not only meeting the degradation speed requirements of most clinical requirements, but also achieving better mechanical properties.

Compared with the prior art, the ureteral stent has the following advantages: 1) the biodegradation speed can be regulated and controlled at will, and after the drainage and supporting actions are finished, the biodegradable film is degraded, broken and disintegrated and discharged out of the body; 2) sufficient mechanical properties, ensuring sufficient drainage, support and fixation effects; 3) the size is stable after molding, and the fixing effect is reliable; 4) is soft and elastic, and ensures no fracture and comfort of patients.

Drawings

FIG. 1 DSC thermogram spectra of PLC materials, PGC materials and PLC/PGC composite materials of the present invention;

fig. 2 is a schematic structural diagram of the degradable ureteral tubular stent obtained in example 5, wherein 1 is a ureteral stent tube; 2 is a curled pipe tail; 3 is a drainage hole;

FIG. 3 is a microfibrous structure of a product obtained when the PLC/PGC composite material is extrusion molded;

fig. 4 is a schematic diagram of cracking of a degradable ureteral stent when the degradable ureteral stent is degraded.

Detailed Description

EXAMPLE 1 preparation of L-lactide/epsilon-caprolactone copolymer

540 g of the product is purified by recrystallizationL-lactide (LLA) and 500 g of epsilon-caprolactone monomer (CL) which is processed by vacuum dehydration and purification are placed in a 5000ml reactor, then 0.015 percent of stannous octoate catalyst is added, and polymerization reaction is carried out for 24 hours at 150 ℃ under the protection of nitrogen, thus obtaining the L-lactide/epsilon-caprolactone copolymer. The copolymer was dissolved in methylene chloride, precipitated with ethanol, and the precipitate was dried in a vacuum desiccator at 60 ℃ for 48 hours to give L-lactide/ε -caprolactone copolymer 1(PLC 1). Preparing the product into a chloroform solution with the concentration of 0.1 percent by weight, and testing the intrinsic viscosity of the solution at 30 ℃ by using an Ubbelohde viscometer; using deuterated chloroform as solvent and nuclear magnetism ¹ H spectrum determination of the proportion of L-lactide and epsilon-caprolactone chain segments; the materials are made into dumbbell strips with the thickness of 1mm or 2mm on a flat vulcanizing machine at the temperature of 140-170 ℃ by a hot press molding method, and the tensile strength and the elongation at break of the dumbbell strips are tested at the tensile speed of 200mm/min or 500 mm/min; testing the Shore A value of the material by using a Shore durometer; the in-vitro degradation experiment of the material is carried out in phosphate buffer solution at 37 ℃, and the time when the sample cannot be clamped by the clamp when the tensile strength is tested after degradation is the strength maintaining time. Determination of the recovery rate of the material from tensile deformation: the dumbbell piece specimen was held in the chuck of the tester for a time of 15s to 100% elongation and this elongation was maintained for 10 min. Releasing load immediately after 10min to allow it to recover freely for 10min, and measuring the recovery rate of tensile deformation within gauge length, wherein E is 1-100 (L-L) ₍₀₎ )/L ₍₀₎ L is the length after free recovery for 10min, L ₍₀₎ Is the original length.

In the same manner as above, copolymers having different molar ratios of monomers were obtained, and the results of the property test are shown in Table 1.

TABLE 1

As can be seen from Table 1, as the content of L-lactide monomer in the copolymer increased, the tensile strength increased, the elongation at break decreased, the hardness also increased, and the degradation strength remained long. It is shown that epsilon-caprolactone units can provide flexibility and that L-lactide units can provide mechanical strength. As can be seen from the deformation recovery rate data in Table 1, the copolymerization ratio of L-lactide and epsilon-caprolactone is in the above range, which can ensure that the material has the elastomer performance, and can keep the rebound resilience of different degrees after being stretched by 100%. When the CL content in the PLC copolymer material exceeds 50% of the molar ratio, the Shore hardness A of the material is too low, and the tensile strength of the material is also obviously reduced; when the CL content is lower than 27 percent of molar ratio, the Shore hardness A of the material is too high, and the deformation recovery rate is also greatly reduced, so that the material is not suitable for being used as a ureter stent material.

EXAMPLE 2 preparation of glycolide/epsilon-caprolactone copolymer

540 g of glycolide monomer (GA) subjected to recrystallization purification treatment and 480 g of epsilon-caprolactone monomer (CL) subjected to vacuum dehydration purification treatment are placed in a 3000ml reactor, 0.02% of stannous octoate catalyst is added, the temperature of the system is raised to 150 ℃ under the protection of nitrogen for reaction for 1 hour, the temperature is raised to 180 ℃ for reaction for 12 hours, the polymer is transferred out of the reactor and further crushed into particles smaller than 3mm, and the particles are placed in a vacuum oven at 90 ℃ for vacuum drying for 50 hours to remove the reacted monomer, so that the glycolide/epsilon-caprolactone copolymer 1(PGC1) is obtained. Preparing the product into a hexafluoroisopropanol solution with the weight ratio of 0.1%, and testing the intrinsic viscosity of the hexafluoroisopropanol solution at 30 ℃ by using an Ubbelohde viscometer; using hexafluoroisopropanol as solvent, with nuclear magnetism ¹ H spectrum determination of glycolide and epsilon-caprolactone chain segment ratio; the materials are made into dumbbell strips with the thickness of 1mm or 2mm on a flat vulcanizing machine at the temperature of 140-170 ℃ by a hot press molding method, and the tensile strength and the elongation at break of the dumbbell strips are tested at the tensile speed of 200mm/min or 500 mm/min; testing the Shore A value of the material by using a Shore durometer; the in-vitro degradation experiment of the material is carried out in phosphate buffer solution at 37 ℃, and the time when the sample cannot be clamped by the clamp when the tensile strength is tested after the material is degraded is the strength maintaining time.

The copolymer with different monomer molar ratios is obtained by polymerizing for 15 to 24 hours at 170 to 190 ℃ by the same method, and the performance test results are shown in Table 2.

TABLE 2

As can be seen from Table 2, the degradation rate of glycolide/epsilon-caprolactone copolymer was significantly faster and the strength was maintained for a shorter period of time than that of L-lactide/epsilon-caprolactone copolymer. In addition, the intrinsic viscosity of the material also has a large influence on the strength and strength retention time of the material. As can be seen from the deformation recovery rate data in Table 2, the copolymerization ratio of glycolide and epsilon-caprolactone is in the above range, so that the material can have elastomer performance, and can maintain resilience of different degrees after being stretched by 100%. When the CL content in the PGC copolymer material exceeds 50% of the molar ratio, the Shore hardness A of the material is too low, and the tensile strength of the material is also obviously reduced; when the CL content is lower than 30 percent of molar ratio, the Shore hardness A of the material is too high, and the deformation recovery rate is also greatly reduced, so that the material is not suitable for being used as a ureter stent material.

EXAMPLE 3 preparation of L-lactide/epsilon-caprolactone copolymer and glycolide/epsilon-caprolactone copolymer composites (PLC/PGC)

300 g of the L-lactide/epsilon-caprolactone copolymer 1(PLC1) and 100 g of glycolide/epsilon-caprolactone copolymer (PGC1) are dissolved in a dichloromethane solution, the mixture is stirred and mixed uniformly, then the blended polymer solution is mixed with a precipitator ethanol, and the precipitated polymer is washed and dried in vacuum at 60 ℃ for 48 hours to obtain the PLC/PGC composite material 1. The dumbbell strips are made from the materials by a hot-press molding method on a flat vulcanizing machine at the temperature of 140-170 ℃. The composite was tested for tensile strength, elongation at break, shore a hardness, and strength retention time as in example 1. The preparation of the PLC/PGC composite material can also be realized by the following method.

The L-lactide/epsilon-caprolactone copolymer and the glycolide/epsilon-caprolactone copolymer prepared in the above examples 1 and 2 are prepared according to the required proportion, the melt blending and the melt extrusion are realized by a double-screw extruder with the screw diameter of 18mm, the process temperature is 110-170 ℃, finally, the materials are granulated to prepare granular materials, and then the dumbbell strips are prepared according to the hot-press molding method. The composite was tested for tensile strength, elongation at break, shore a value, material tensile set recovery and strength retention time as in example 1, while compatibility of its blend was characterized by Differential Scanning Calorimetry (DSC).

Using the same method (solution blending method) as above, PLC/PGC composite materials were obtained containing different weight percentages of PLC and PGC, and the results of the performance tests are shown in Table 3.

TABLE 3

As can be seen from Table 3, comparing tables 1 and 2, the PLC/PGC composites have a significantly higher tensile strength than the PLC, intermediate between the PLC and PGC, because of their good compatibility, and DSC thermal analysis demonstrated that they have only one glass transition temperature, as shown in FIG. 1. It can also be seen from table 3 that the in vitro degradation rate of the composite material increases with the glycolide/epsilon-caprolactone copolymer (PGC) content, such as composite materials 3, 4, 5, 6 and 7, and thus can be arbitrarily controlled as required. In addition, the deformation recovery rate of the PLC/PGC composite material is higher than that of the PLC material, and the PLC/PGC composite material is predicted to have better elastic recovery performance. The shore a and elongation at break of the composites were not much changed from their individual materials of the same lot, and were within the usable range.

The PLC/PGC composite material only shows one glass transition temperature, which shows that the PLC and PGC materials have good compatibility.

EXAMPLE 4 preparation of L-lactide/epsilon-caprolactone copolymer, glycolide/epsilon-caprolactone copolymer and barium sulfate blended composite

300 g of the L-lactide/epsilon-caprolactone copolymer and 100 g of the glycolide/epsilon-caprolactone copolymer obtained in examples 1 and 2 were dissolved in a methylene chloride solution, and 100 g of barium sulfate (BaSO) ₄ Particle size of 0.5-5 μm) is uniformly dispersed in the solution under the action of ultrasound, ethanol is used as a precipitator to obtain a barium sulfate composite material (composite material Ba), and the barium sulfate is compoundedThe material was dried under vacuum at 60 ℃ for 48 hours. The dumbbell strips are made from the materials by a hot-press molding method on a flat vulcanizing machine at the temperature of 140-170 ℃. The composite was tested for tensile strength, elongation at break, shore a hardness, and strength retention time as in example 1. The preparation of the barium sulfate composite material can also be realized by the following method.

The L-lactide/epsilon-caprolactone copolymer and the glycolide/epsilon-caprolactone copolymer prepared in the above examples 1 and 2 and barium sulfate are prepared according to the required proportion, the melt blending and the melt extrusion are realized by a double-screw extruder with the screw diameter of 18mm, the process temperature is 110-170 ℃, finally, the materials are granulated to prepare granular materials, and then the dumbbell sheet strips are prepared according to the hot press molding method. The barium sulfate composite (composite Ba) was tested for tensile strength, elongation at break, shore a hardness, and strength retention time as in example 1.

The composition ratios and the performance test results of the barium sulfate composite materials prepared by the same methods as described above are shown in Table 4.

Control test 1

400 g of the L-lactide/epsilon-caprolactone copolymer (PLC3) prepared in example 1 and crosslinked polyvinylpyrrolidone (PVPP, particle size 5-50 mu m, trade name: PolyKoVidone ^TM )10 g and 90 g of barium sulfate, and then melt blending and melt extrusion are realized through a double-screw extruder with the screw diameter of 18mm, the process temperature is 150 ℃, finally, the mixture is granulated to prepare a granular composite material (composite material PVPP), and then the dumbbell sheet strip is prepared according to the hot-press forming method. The composite was tested for tensile strength, elongation at break, shore a hardness, and strength retention time as in example 1.

TABLE 4

In Table 4, the mechanical properties of the composite material Ba1 formed by PLC1 and PGC1 are not changed by adding BaSO ₄ The tensile strength of the affected part is higher than that of PLC1 alone and is 7.6 MPa; body thereofThe strength maintenance time of the external degradation was accelerated compared to that of PLC 1; the hardness did not change much, indicating that the flexibility did not change much. The barium sulfate composite materials Ba2 and Ba3 have similar change rules. The composite material PVPP in control 1, with the addition of crospovidone, had a faster degradation rate (degradation strength retention time of 71 days) than that of PLC3, but was far less than composite material Ba2 (degradation strength retention time of 29 days) using the same material PLC3, and had a tensile strength much lower than composite material Ba2, even lower than that of PLC 3.

Example 5 preparation of degradable ureteral stents

The composite material prepared in the above embodiment is extruded and molded by a single screw extruder to obtain the tubular ureter stent. The extrusion temperature is within the range of 100-160 ℃, the temperature of an extruder head is set to be 110-155 ℃, and the rotating speed of a screw is set to be 10-15 r/min. The outer diameter of the tubular body 1 of the tubular object obtained by molding is 1.7mm, and the inner diameter is 1.1 mm. The degradable ureteral stent is characterized in that a coiled tube tail 2 with two ends or one end is formed by secondary forming, and drainage holes 3 are formed after the tube is punched at equal intervals (the hole distance is 50mm) (the longitudinal hole diameter is 1.5mm) by punching equipment, and the degradable ureteral stent is shown in figure 2. Their tensile strength, elongation at break, and strength retention time of in vitro degradation in a phosphate buffer solution at 37 ℃ and dimensional shrinkage in the length direction after 24-hour immersion in a phosphate buffer solution at 37 ℃ are shown in Table 5. In table 5, as a control, the ureteral stent of the present invention and the polyurethane non-degradable ureteral stent were subjected to comparative tests for mechanical properties.

Control 2, with reference to the method disclosed in CN 103041454A, 10 g of crosslinked polyvinylpyrrolidone (PVPP, particle size 5-50 μm, trade Mark: PolyKoVidone) ^TM ) 90 g of barium sulfate were uniformly dispersed in 4L of an acetone solution containing 400 g of L-lactide/epsilon-caprolactone copolymer (PLC3) in a monomer molar ratio of 60:40 and an intrinsic viscosity of 1.7dl/g by ultrasonication. The composite material was obtained by precipitation with 8L ethanol. Vacuum drying the composite material for 48 hours to obtain the single snailThe rod extruder performs extrusion. The extrusion temperature was 150 ℃, the temperature of the extruder head was set at 160 ℃ and the screw speed was set at 10 rpm. The external diameter of the molded ureteral stent is 1.7mm, and the internal diameter is 1.1 mm. The mechanical properties and the retention time of the degradation strength are shown in Table 5.

TABLE 5

The results show that the tensile strength of the ureteral stents 5, 6, 7, 8, 9 and 10 prepared from the composite materials of the L-lactide/epsilon-caprolactone copolymer and the glycolide/epsilon-caprolactone copolymer is obviously greater than that of the ureteral stent 1 and the ureteral stent 2 prepared from the L-lactide/epsilon-caprolactone copolymer; the degradation strength maintaining time is between two single materials, and can be randomly regulated and controlled according to different blending ratios of the two single materials; and the size shrinkage rate is obviously reduced and is equivalent to that of a polyurethane ureter bracket. The invention discovers that the mechanical property and the dimensional stability of the degradable ureteral stent made of the composite material are improved because PGC has stronger crystallization tendency, and the PGC forms orderly arranged microfine fibers under the action of tensile stress generated during extrusion molding, as shown in figure 3, and the fibers contained in the stent tube can play a good role in reinforcing and stabilizing the degradable ureteral stent. When the ureteral stent is degraded to a certain extent, the tube is cracked in an axial splitting way and is not sticky, as shown in figure 4, and the inner part of the tube is further proved to have an axially-arranged microfiber structure, and the degradation mode is favorable for the ureteral stent to be discharged out of a ureteral cavity channel. The ureteral stents made of the L-lactide/epsilon-caprolactone copolymer and the glycolide/epsilon-caprolactone copolymer alone did not show the formation of the microfibrous.

Control 2 ureteral stents also accelerated the degradation of PLC to some extent due to the addition of cross-linked polyvinylpyrrolidone (PVPP), but the tensile strength was reduced. Compared with the ureteral stent in the comparison test 2, the degradable ureteral stent has better mechanical properties of the degradable ureteral stents 5, 6 and 7 under the same PLC material, the degradation maintenance time can be adjusted to be shorter, the processed size is more stable, and the requirement of the clinically needed degradation time is better met.

Claims

1. A degradable ureteral stent is of a round tubular structure, and is characterized in that the degradable ureteral stent is made of a composite material formed by blending at least the following two degradable high polymer materials:

1) the copolymer is formed by random copolymerization of L-lactide and epsilon-caprolactone, and the weight percentage content of the copolymer is 20-95%;

2) the copolymer is formed by random copolymerization of glycolide and epsilon-caprolactone, and the weight percentage of the copolymer is 5-80%;

in terms of mole number, in the L-lactide/epsilon-caprolactone copolymer, epsilon-caprolactone accounts for 25% -50%, L-lactide accounts for 50% -75%;

in terms of mole number, in the glycolide/epsilon-caprolactone copolymer, epsilon-caprolactone accounts for 30-50%, and glycolide accounts for 50-70%;

the intrinsic viscosity of the L-lactide/epsilon-caprolactone copolymer in chloroform at 30 ℃ is 1.2-3.0 dl/g;

the intrinsic viscosity of the glycolide/epsilon-caprolactone copolymer in hexafluoroisopropanol at 30 ℃ is 1.0-2.0 dl/g.

2. The degradable ureteral stent according to claim 1, wherein the degradable ureteral stent is a hollow round tubular structure, the outer diameter of the tube is 1.0-3.2 mm, and the inner diameter of the tube is 0.6-2.0 mm.

3. The degradable ureteral stent according to claim 1, wherein, on the basis of the round tubular structure, the stent is formed by secondary molding to have fixing structures at two ends or one end for preventing sliding;

wherein, the fixed structure of one end is used for fixing at the position of renal pelvis, and the fixed structure of the other end is used for fixing at the position of bladder.

4. The degradable ureteral stent according to claim 3, wherein the fixing structure of the degradable ureteral stent is a coil shape, and the coil shape is a circular coil shape or a semicircular coil shape;

the curly shape is formed by curling a round tube shape, and the middle part is hollow.

5. The degradable ureteral stent according to claim 1, wherein a plurality of drainage side holes are formed through the wall of the tubular stent on the basis of the shape of a round tube;

the drainage side holes are equidistant or unequal, and the drainage side holes are circular or elliptical.

6. The degradable ureteral stent according to claim 1, wherein the degradable ureteral stent is made of a blended composite material comprising 30 to 80 weight percent of L-lactide/epsilon-caprolactone copolymer and 20 to 70 weight percent of glycolide/epsilon-caprolactone copolymer.

7. The degradable ureteral stent according to any one of claims 1 to 6, further comprising a radiopaque medical imaging agent;

the medical developer is barium sulfate.

8. The degradable ureteral stent according to any one of claims 1 to 6, wherein the composite material has a tensile strength of more than 10MPa, an elongation at break of more than 300%, and a Shore hardness A ranging from 40 to 100.