Degradable ureteral stent and preparation method thereof

Abstract

The invention relates to a degradable ureteral stent and a preparation method thereof. The degradable ureteral stent disclosed by the invention comprises hydrogel with a double-network structure, and the hydrogel with the double-network structure comprises a network structure formed by a polyethylene glycol diacrylate cross-linked polymer and a network structure formed by polyvinyl alcohol, the polyethylene glycol diacrylate cross-linked polymer is formed by cross-linking polyethylene glycol diacrylate and an optional cross-linking agent; the network structure formed by polyvinyl alcohol is a network structure formed by mutually entangling polyvinyl alcohol molecular chains and optionally entangling the polyvinyl alcohol molecular chains with the network structure formed by the polyethylene glycol diacrylate cross-linked polymer. The degradable ureteral stent disclosed by the invention is a degradable ureteral stent which has good biocompatibility and can simultaneously take both the mechanical property and the in-vivo degradability into consideration.

Description

Technical Field

[0001] The present invention relates to a degradable ureteral stent and a preparation method thereof, and more particularly to a ureteral stent made of a hydrogel material and a preparation method thereof, belonging to the field of biomedical materials and medical devices. Background Art

[0002] Ureteral stents are key medical devices commonly used in urology to treat diseases such as kidney stones, urinary tract obstruction, and ureteral stenosis. Their main function is to maintain urethral patency and promote urine excretion. Existing ureteral stents are mostly made of non-degradable materials such as silicone or polyurethane, which have poor biocompatibility. Long-term implantation in the body may cause adverse reactions such as local inflammation and infection. In addition, patients need to undergo a second operation to remove the stent, which not only increases the patient's treatment burden, but also aggravates the waste of medical resources. Therefore, the research and development of ureteral stents that can be degraded in the body is imminent.

[0003] In the prior art, a variety of degradable materials have been used to prepare degradable ureteral stents. However, there are many problems in terms of the production cost and ease of production process of the ureteral stents, as well as the induction of inflammation during ureteral stent degradation and the controllability of the degradation rate.

[0004] For example, in Patent Document 1, the material used to prepare the degradable ureteral stent is polylactic acid-glycolic acid copolymer. This type of material may release acidic degradation products during the degradation process, and the acidification of the local environment may trigger an inflammatory response.

[0005] In Patent Document 2, the various materials involved in the preparation of the degradable ureteral stent (such as polymers and inorganic fillers) have poor interfacial compatibility during the composite process, which may lead to material stratification or uneven degradation, and the preparation is highly complex, which may lead to high costs for large-scale production.

[0006] In Patent Document 3, the material used to prepare the degradable ureteral stent is a degradable thermoplastic polymer (polycaprolactone) material. This material may face the problems of narrow processing temperature window and sensitive preparation parameters during the stent preparation process.

[0007] In Patent Document 4, the material used to prepare the degradable ureteral stent is a natural polymer material (such as chitosan or gelatin), the degradation rate of which is difficult to accurately control in urine and may be greatly affected by the pH value, temperature and enzyme activity of the body fluid.

[0008] In recent years, hydrogels have attracted widespread attention as an ideal biodegradable material due to their excellent biocompatibility, flexibility, and adjustable hydration capacity. Their high water content and biological tissue-like properties make them a promising material for ureteral stents. However, conventional hydrogels often struggle to balance mechanical properties and degradability, hindering their application in medical devices. Therefore, developing a hydrogel scaffold that can provide both good mechanical support and controllable degradation in vivo has become a research hotspot.

[0009] Citations

[0010] Patent Document 1: CN110065186B

[0011] Patent Document 2: CN109758620B

[0012] Patent Document 3: CN115154664A

[0013] Patent Document 4: JP3233978U Summary of the Invention

[0014] Problems to be solved by the invention

[0015] In view of the above problems existing in the prior art, the technical problem to be solved by the present invention is to provide a degradable ureteral stent with good biocompatibility and capable of taking into account both mechanical properties and degradability in the body, as well as a preparation method of the degradable ureteral stent.

[0016] Solutions for solving problems

[0017] To address the above-mentioned deficiencies in the prior art, the present invention provides a degradable ureteral stent, which is a hydrogel ureteral stent based on a double network structure of a cross-linked polymer of polyvinyl alcohol (PVA) and polyethylene glycol diacrylate (PEGDA). This degradable ureteral stent solves the above-mentioned technical problems.

[0018] In addition, the present invention also provides a method for preparing the above-mentioned degradable ureteral stent, which overcomes the problems existing in the above-mentioned preparation method.

[0019] Specifically, the present invention solves the problems of the present invention through the following solutions.

[0020] [1] A degradable ureteral stent, wherein the degradable ureteral stent comprises a double network structure hydrogel, wherein the double network structure hydrogel comprises a network structure formed by a polyethylene glycol diacrylate cross-linked polymer and a network structure formed by polyvinyl alcohol, wherein the polyethylene glycol diacrylate cross-linked polymer is formed by cross-linking polyethylene glycol diacrylate and an optional cross-linking agent, and the network structure formed by polyvinyl alcohol is a network structure formed by polyvinyl alcohol molecular chains entangled with each other and optionally entangled with the network structure formed by the polyethylene glycol diacrylate cross-linked polymer.

[0021] [2] The degradable ureteral stent according to [1], wherein, in the double-network structure hydrogel, the mass ratio of the polyvinyl alcohol to the polyethylene glycol diacrylate cross-linked polymer is (0.20-0.45):1; the weight average molecular weight of the polyvinyl alcohol is 70,000-130,000, preferably 85,000-124,000; the weight average molecular weight of the polyethylene glycol diacrylate is 900-7,000, preferably 1,000-6,000.

[0022] [3] The degradable ureteral stent according to [1] or [2], wherein the water content is 60% to 75% by mass relative to the total mass of the double-network structure hydrogel.

[0023] [4] The degradable ureteral stent according to any one of [1] to [3], wherein the cross-linking agent is N,N'-methylenebisacrylamide and / or hydroxyethyl methacrylate; and the mass ratio of the polyethylene glycol diacrylate to the cross-linking agent is 100:(0-6), preferably 100:(1-5).

[0024] [5] The degradable ureteral stent according to any one of [1] to [4], wherein the double network structure hydrogel further comprises an additive; the content of the additive is 5% by mass or less, preferably 3% by mass or less, relative to the total mass of the double network structure hydrogel; and the additive is one or more selected from antibacterial agents, medical developers, plasticizers, lubricants and dyes.

[0025] [6] The degradable ureteral stent according to any one of [1] to [5], wherein the degradable ureteral stent is in the shape of a circular tube; the outer diameter of the degradable ureteral stent is 1.4 to 3.2 mm, and the inner diameter is 1.0 to 2.0 mm.

[0026] [7] A method for preparing a degradable ureteral stent according to any one of [1] to [6], comprising the following steps:

[0027] Step 1: adding polyethylene glycol diacrylate, a photoinitiator, and optionally the crosslinking agent and the additives to a polyvinyl alcohol aqueous solution and mixing them uniformly to prepare a hydrogel precursor solution;

[0028] Step 2: The hydrogel precursor solution prepared in step 1 is coaxially extruded into an ultraviolet light irradiation environment to obtain the degradable ureteral stent.

[0029] [8] The method for preparing a degradable ureteral stent according to [7], wherein, in the polyvinyl alcohol aqueous solution, the mass ratio of the polyvinyl alcohol to the water is 0.7:9.3 to 3:7, preferably 1:9 to 2:8; the preparation method further comprises dissolving the polyvinyl alcohol in water under heating conditions to obtain the polyvinyl alcohol aqueous solution; the heating conditions are a heating temperature of 75°C to 95°C, preferably a heating temperature of 80°C to 90°C.

[0030] [9] The method for preparing a degradable ureteral stent according to [7] or [8], wherein the photoinitiator is one or more selected from 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropenone, 1-hydroxycyclohexylphenyl ketone, 2-isopropylthioxanthone, and 2,4,6-trimethylbenzoyl-diphenylphosphine oxide; and in step 1, the ratio of the added amounts of the polyethylene glycol diacrylate, the photoinitiator, and the cross-linking agent is 100:(0.5-6):(0-6) by mass, preferably 100:(1-5):(1-5).

[0031]

[10] The method for preparing a degradable ureteral stent according to any one of [7] to [9], wherein, in step 2, the coaxial extrusion is performed using a coaxial needle; the hydrogel precursor solution is extruded into a transparent silicone tube through the coaxial needle, and the transparent silicone tube is irradiated with ultraviolet light; the wavelength of the ultraviolet light is 253 nm to 385 nm, and the intensity of the ultraviolet light is 800 to 2000 W / cm 2 , the UV irradiation time is 60s to 4s.

[0032] Effects of the Invention

[0033] The degradable ureteral stent of the present invention has at least the following outstanding beneficial effects compared to the prior art:

[0034] First, the degradable ureteral stent prepared by the present invention has the characteristics of good biocompatibility. The materials used, polyvinyl alcohol and polyethylene glycol diacrylate, have passed the inspection and certification of the U.S. Food and Drug Administration (FAD) and have no residual toxic monomers and reaction by-products.

[0035] Second, the degradable ureteral stent prepared by the present invention has the characteristics of good mechanical properties and controllable degradation rate, and is suitable for short-term and long-term applications in maintaining ureteral patency.

[0036] Third, the degradable ureteral stent prepared by the present invention has a good lubricating effect, which is helpful in alleviating the patient's discomfort during surgical implantation.

[0037] The preparation method of the degradable ureteral stent of the present invention has at least the following outstanding beneficial effects compared with the prior art:

[0038] The preparation method of the degradable ureteral stent of the present invention is simple and rapid, with a short preparation cycle, and is conducive to batch production. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is a schematic diagram of step 2 in the method for preparing a degradable ureteral stent of the present invention.

[0040] Figure 2 This is a graph showing the change in the remaining mass percentage of the hydrogel tube sample of Example 1 in artificial urine over time.

[0041] Figure 3 Graph showing the change in the remaining mass percentage of the hydrogel tube samples of Example 1, Example 2 and Comparative Example 1 in artificial urine over time.

[0042] Figure 4 1 and 2 are microstructure diagrams of the surfaces of the hydrogel tube samples of Example 1, Example 2, and Comparative Example 1, respectively.

[0043] Figure 5 Graph showing the tensile properties test results of the tensile strips of Example 1, Example 2, and Comparative Example 1.

[0044] Figure 6 Graph showing the compression performance test results of the hydrogel tube samples of Example 1, Example 2, and Comparative Example 1.

[0045] Figure 7 1 is a cross-sectional view showing the hydrogel ureteral stent prepared in Example 1. DETAILED DESCRIPTION

[0046] The following describes the technical features of the present invention in detail. The technical features described below are described based on representative embodiments and specific examples of the present invention, but the present invention is not limited to these embodiments and specific examples.

[0047] <Terms and Definitions>

[0048] In this specification, "room temperature" refers to a temperature range of 20 to 30°C, for example, 25°C.

[0049] In this specification, the numerical range expressed using "a numerical value A to a numerical value B" means a range including the endpoints A and B.

[0050] In this specification, the numerical range expressed using "above" or "below" means a numerical range including the number.

[0051] In this specification, the use of "may" includes both the meaning of performing a certain process and the meaning of not performing a certain process.

[0052] In this specification, "optionally" or "optional" is used to indicate that certain substances, components, execution steps, application conditions and other factors are used or not used.

[0053] In this specification, the unit names used are all international standard unit names, and unless otherwise stated, the "%" used means weight or mass percentage.

[0054] In this specification, references to "preferred embodiments," "embodiments," and the like mean that the specific elements (e.g., features, structures, properties, and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein and may or may not be present in other embodiments. In addition, it should be understood that the elements may be combined in any suitable manner in the various embodiments.

[0055] First embodiment

[0056] One of the objects of the present invention is to provide a degradable ureteral stent, wherein the degradable ureteral stent comprises a double-network structure hydrogel, wherein the double-network structure hydrogel comprises a network structure formed by a polyethylene glycol diacrylate cross-linked polymer and a network structure formed by polyvinyl alcohol, wherein the polyethylene glycol diacrylate cross-linked polymer is formed by cross-linking polyethylene glycol diacrylate and an optional cross-linking agent, and the network structure formed by polyvinyl alcohol is a network structure formed by polyvinyl alcohol molecular chains entangled with each other and optionally entangled with the network structure formed by the polyethylene glycol diacrylate cross-linked polymer.

[0057] The dual network structure of the dual network hydrogel is explained as follows: On the one hand, polyethylene glycol diacrylate (PEGDA) and an optional crosslinking agent are crosslinked to form a rigid three-dimensional network structure, i.e., a network structure formed by a crosslinked polyethylene glycol diacrylate polymer; here, when crosslinking occurs, the polyethylene glycol diacrylate itself can act as a crosslinking agent; in the absence of an additional crosslinking agent, the polyethylene glycol diacrylate itself crosslinks, and when an additional crosslinking agent is added, both the additional crosslinking agent and the polyethylene glycol diacrylate can act as crosslinking agents when crosslinking occurs. On the other hand, the polyvinyl alcohol (PVA) molecular chains have good flexibility, so the polyvinyl alcohol molecular chains entangle with each other and optionally with the network structure formed by the crosslinked polyethylene glycol diacrylate polymer to form a network structure.

[0058] The degradable ureteral stent of the present invention comprises a double-network structure hydrogel based on polyvinyl alcohol / polyethylene glycol diacrylate cross-linked polymer (hereinafter also referred to as double-network structure hydrogel), so that the prepared hydrogel ureteral stent can simultaneously take into account both mechanical properties and in vivo degradability. As for in vivo degradability, the ureteral stent can be completely degraded in the body; in addition, polyvinyl alcohol and polyethylene glycol diacrylate are both FDA-certified highly biocompatible and highly biosafe materials, and these raw materials do not contain residual toxic monomers and reaction byproducts.

[0059] Specifically, the polyvinyl alcohol (PVA) used in the biodegradable ureteral stent of the present invention exhibits excellent mechanical strength, hydration properties, and biodegradability, while polyethylene glycol diacrylate (PEG) crosslinks upon UV light to form a stable three-dimensional network structure, further enhancing the hydrogel's mechanical properties and stability. The PEG / PEG diacrylate crosslinked polymer dual-network hydrogel material, due to its combination of two network structures, offers both high mechanical strength and good biodegradability.

[0060] Furthermore, the present invention uses ultraviolet light to initiate covalent crosslinking to construct a uniform double-network hydrogel, which degrades more evenly and at a more stable rate. For example, after being immersed in artificial urine at 37°C for 4 weeks, the hydrogel can still maintain its original shape without dissociation. For details, please refer to Examples 1 and Figure 2 .

[0061] Various aspects of the biodegradable ureteral stent of the present invention are described in detail below.

[0062] In some preferred embodiments, in the double-network structure hydrogel, the mass ratio of polyvinyl alcohol to polyethylene glycol diacrylate cross-linked polymer is (0.20-0.45):1, preferably (0.23-0.40):1.

[0063] In a first embodiment of the present invention, the mechanical properties and in vivo degradation rate of the prepared degradable ureteral stent can be adjusted by adjusting the mass ratio of polyvinyl alcohol to polyethylene glycol diacrylate cross-linked polymer in the double-network hydrogel. For example, by increasing the mass ratio of polyvinyl alcohol to polyethylene glycol diacrylate cross-linked polymer, the in vivo degradation rate of the degradable ureteral stent can be increased, while the mechanical properties of the degradable ureteral stent will be reduced. Conversely, by decreasing the mass ratio of polyvinyl alcohol to polyethylene glycol diacrylate cross-linked polymer, the mechanical properties of the degradable ureteral stent can be improved, while the in vivo degradation rate of the degradable ureteral stent will be reduced.

[0064] In some preferred embodiments, the weight average molecular weight of the polyvinyl alcohol is 70,000 to 130,000, preferably 85,000 to 124,000.

[0065] In some preferred embodiments, the weight average molecular weight of polyethylene glycol diacrylate is 900-7000, preferably 1000-6000, more preferably 1000-5000.

[0066] In some preferred embodiments, in the degradable ureteral stent, the water content is 60% to 75% by mass, preferably 63% to 72% by mass, for example, 65%, 67%, 69% and 70% by mass, relative to the total mass of the double-network structure hydrogel.

[0067] In some cases, the water content in the double-network structure hydrogel of the degradable ureteral stent of the present invention is variable. For example, as the storage time increases, the water may be partially lost, but this does not affect the achievement of the purpose of the present invention.

[0068] When implanting a degradable ureteral stent, if the water content is lower than the above range, the water content can be increased by soaking the degradable ureteral stent in water; if the water content is higher than the above range, the water content can be reduced by squeezing or other operations.

[0069] In some preferred embodiments, the crosslinking agent is N,N'-methylenebisacrylamide and / or hydroxyethyl methacrylate.

[0070] In some preferred embodiments, the mass ratio of polyethylene glycol diacrylate to the cross-linking agent is 100:(0-6), preferably 100:(1-5).

[0071] In some preferred embodiments, the double network structure hydrogel includes additives; preferably, the content of the additive is 5 mass% or less, preferably 3 mass% or less, relative to the total mass of the double network structure hydrogel; further preferably, the additive is one or more selected from antibacterial agents, medical developers, plasticizers, lubricants and dyes.

[0072] In some preferred embodiments, the degradable ureteral stent is in the shape of a round tube.

[0073] The present invention does not particularly limit the inner and outer diameters of the degradable ureteral stent (circular tube), and can be selected based on the patient's needs. In some preferred embodiments, the outer diameter of the degradable ureteral stent (circular tube) is 1.4 to 3.2 mm, and the inner diameter is 1.0 to 2.0 mm; preferably, the outer diameter of the degradable ureteral stent (circular tube) is 1.6 to 3.2 mm, and the inner diameter is 1.5 to 2.0 mm.

[0074] In some preferred embodiments, the wall thickness of the degradable ureteral stent (circular tube) (i.e., (ureteral stent outer diameter - ureteral stent inner diameter) / 2) is 0.2 mm to 0.6 mm, preferably 0.3 mm to 0.5 mm, for example, 0.4 mm. The wall thickness can be selected based on, for example, the desired residence time of the ureteral stent in the body and / or the desired compressive strength.

[0075] The present invention does not specifically limit the length of the biodegradable ureteral stent; the length can be selected based on specific needs. For example, the length of a ureteral stent for adults is typically 24 cm to 30 cm, such as 25 cm, 26 cm, 27 cm, 28 cm, and 29 cm; the length of a ureteral stent for children is typically 14 cm to 20 cm, such as 15 cm, 16 cm, 17 cm, 18 cm, and 19 cm. Furthermore, the length of the ureteral stent can be adjusted for patients with special needs.

[0076] The degradation process of the degradable ureteral stent of the present invention in vivo (e.g., in the human body) depends not only on urine, but also on the ureteral tissue in contact with the stent and the in vivo environment (pH value, etc.), which can be demonstrated by the test in Example 1 below.

[0077] The degradable ureteral stent of the present invention can be obtained by the preparation method described in the second embodiment below.

[0078] Second embodiment

[0079] Another object of the present invention is to provide a method for preparing the degradable ureteral stent of the present invention, the preparation method comprising the following steps:

[0080] Step 1: adding polyethylene glycol diacrylate, a photoinitiator, and optionally the crosslinking agent and the additives to a polyvinyl alcohol aqueous solution and mixing them uniformly to prepare a hydrogel precursor solution;

[0081] Step 2: The hydrogel precursor solution prepared in step 1 is coaxially extruded into an ultraviolet light irradiation environment to obtain the degradable ureteral stent.

[0082] The preparation method of the degradable ureteral stent of the present invention selects materials with high biocompatibility and high biosafety. Through coaxial extrusion and one-step molding, the structure of the material can be precisely controlled, and ultraviolet light cross-linking can complete the cross-linking reaction in a short time to form a degradable ureteral stent with a stable structure.

[0083] The present invention's method for preparing a degradable ureteral stent utilizes a process combining coaxial extrusion with UV cross-linking technology. This not only ensures the stent's mechanical strength and stability, but also precisely controls its degradation rate to meet clinical treatment needs. Furthermore, the coaxial extrusion process and the composition of the hydrogel material provide the resulting degradable ureteral stent with excellent lubrication, mitigating patient discomfort during surgical implantation.

[0084] The following describes in detail each step of the preparation method of the present invention.

[0085] <Step 1>

[0086] In some preferred embodiments, in the polyvinyl alcohol aqueous solution, the mass ratio of polyvinyl alcohol to water is 0.7:9.3 to 3:7, more preferably 1:9 to 2:8.

[0087] In some preferred embodiments, in step 1, polyethylene glycol diacrylate, a photoinitiator, and optional crosslinking agents and additives are added to the polyvinyl alcohol solution, and the mixture can be uniformly mixed by stirring at a stirring speed of 500 to 1500 rpm, preferably 800 to 1200 rpm.

[0088] In some embodiments, the preparation method of the present invention further comprises dissolving polyvinyl alcohol in water under heating conditions to produce a polyvinyl alcohol aqueous solution. Preferably, the water used can be deionized water; the heating conditions are a heating temperature of 75°C to 95°C, preferably a heating temperature of 80°C to 90°C; further preferably, stirring can be performed to promote the dissolution of the polyvinyl alcohol in the water, and the stirring speed is 500 to 1500 rpm, preferably 800 to 1200 rpm.

[0089] In some preferred embodiments, in step 1, the photoinitiator is one or more selected from 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropenone, 1-hydroxycyclohexylphenyl ketone, 2-isopropylthioxanthone, and 2,4,6-trimethylbenzoyl-diphenylphosphine oxide.

[0090] In some preferred embodiments, in step 1, the ratio of the added amount of polyethylene glycol diacrylate to the added amount of the photoinitiator is 100:(0.5-6) ​​by mass, preferably 100:(1-5).

[0091] In some preferred embodiments, in step 1, the ratio of the added amount of polyethylene glycol diacrylate to the cross-linking agent is 100:(0-6) by mass, preferably 100:(1-5).

[0092] In some preferred embodiments, in step 1, the ratio of the added amounts of polyethylene glycol diacrylate, photoinitiator and crosslinking agent is 100:(0.5-6):(0-6) by mass, preferably 100:(1-5):(1-5).

[0093] <Step 2>

[0094] In step 2, the hydrogel precursor solution prepared in step 1 is coaxially extruded into an ultraviolet light irradiation environment to obtain a degradable ureteral stent. In the presence of a photoinitiator, the polyethylene glycol diacrylate and the optional crosslinking agent readily undergo a crosslinking reaction upon exposure to ultraviolet light. Therefore, in the preparation method of the present invention, after exposure to ultraviolet light in step 2, the polyethylene glycol diacrylate and the optional crosslinking agent are substantially completely converted into a crosslinked polyethylene glycol diacrylate polymer.

[0095] In some preferred embodiments, in step 2, the ultraviolet light irradiation environment is provided by an ultraviolet lamp.

[0096] In some preferred embodiments, in step 2, coaxial extrusion is performed using a coaxial needle. Preferably, the inner diameter of the outer needle of the coaxial needle is 1.4 to 3.2 mm, preferably 1.6 to 3.2 mm, and the outer diameter of the inner needle is 1.0 to 2.0 mm, preferably 1.5 to 2.0 mm. For example, the specifications of the coaxial needle can be: 12G (outer needle) - 16G (inner needle), 11G (outer needle) - 15G (inner needle), etc.

[0097] In the preparation method of the present invention, the specifications of the needle used can be adjusted according to needs (for example, the patient's requirements for the inner diameter and outer diameter of the ureteral stent).

[0098] In some preferred embodiments, in step 2, as Figure 1As shown, a syringe filled with a hydrogel precursor solution is fixed on a booster pump, and the syringe is connected to the outer needle of the coaxial needle. The hydrogel precursor solution is pushed into the space between the outer needle and the inner needle by the booster pump, and further squeezed into the transparent silicone tube connected to the outer needle, and the transparent silicone tube is irradiated by ultraviolet light ( Figure 1 The hydrogel precursor solution is dyed to better illustrate its location within the transparent silicone tube. A silicone core (which can be hollow or solid) is inserted into the inner needle of the coaxial needle. The length of the silicone core significantly exceeds that of the inner needle, allowing it to be inserted into the transparent silicone tube. It should be noted that the outer diameter of the silicone core inserted into the transparent silicone tube can be 1.0 to 2.0 mm, and the inner diameter of the transparent silicone tube is preferably 1.4 to 3.2 mm, more preferably 1.6 to 3.2 mm.

[0099] In some preferred embodiments, in step 2, the wavelength of the ultraviolet light is 253 nm to 385 nm.

[0100] In some preferred embodiments, in step 2, the intensity of the ultraviolet light is 800 to 2000 W / cm 2 .

[0101] In some preferred embodiments, in step 2, the ultraviolet light irradiation time is 60s to 4s.

[0102] The intensity of the ultraviolet light and the ultraviolet irradiation time can be selected as needed. The greater the intensity of the ultraviolet light, the shorter the required ultraviolet irradiation time.

[0103] The degradable ureteral stent prepared by the preparation method of the present invention is usually longer in size (especially in batch production), and the ureteral stent can be cut according to demand.

[0104] In the preparation method of the present invention, the structure, degradability and mechanical properties of the double-network hydrogel can be controlled by adjusting the molecular weights of the raw materials polyvinyl alcohol and polyethylene glycol diacrylate, the amount of photoinitiator and cross-linker added, and the wavelength, intensity and irradiation time of ultraviolet light during ultraviolet light irradiation.

[0105] Example

[0106] The present invention will be further described by enumerating specific embodiments below. It should be understood that these embodiments are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that, after reading the content described in the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms fall within the scope of the present invention.

[0107] The description of the raw materials used in the following examples is as follows:

[0108] Polyvinyl alcohol, produced by Shanghai MacLean Biochemical Technology Co., Ltd., product number: 363081, weight average molecular weight 85000-124000.

[0109] Polyethylene glycol diacrylate, produced by Shanghai Aladdin Biochemical Technology Co., Ltd., product number: P131593, with a weight average molecular weight of approximately 1000, containing 100 ppm 4-methoxyphenol (MEHQ) stabilizer and 300 ppm butylated hydroxytoluene (BHT) stabilizer.

[0110] Photoinitiator: 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropenone, produced by Shanghai MacLean Biochemical Technology Co., Ltd., product number: H823463, CAS number: 106797-53-9.

[0111] Cross-linking agent: N,N'-methylenebisacrylamide, produced by Beijing Bailingwei Technology Co., Ltd., product number: 402847, CAS number: 110-26-9.

[0112] Artificial urine, produced by Beijing Solebow Technology Co., Ltd., product number A6660.

[0113] The following descriptions of the equipment used in the following examples are as follows:

[0114] Syringe: Produced by Kefu Medical Technology Co., Ltd.; Capacity: 1mL

[0115] Coaxial needle: produced by Shanghai Hongshuo Electronics Co., Ltd.; specifications 11G-15G.

[0116] Translucent silicone tube: produced by Shanghai Daoguan Rubber & Plastic Hardware Co., Ltd.; inner diameter 2.5mm, outer diameter 3mm.

[0117] Silicone core: The outer diameter of the part inserted into the transparent silicone tube is 1.8mm.

[0118] UVLED ring surface light curing lamp, produced by Shanghai Futanxi Electronic Technology Co., Ltd., model UVRL-81T.

[0119] Field emission environmental scanning electron microscope, model QUANTA 200FEG, manufactured by FEI Company of the Netherlands.

[0120] Electronic universal testing machine, produced by Shimadzu Corporation of Japan, model EZ-LX HS.

[0121] Video contact angle measuring instrument, model OCA-20, produced by Dataphysics Instruments, Germany.

[0122] Example 1

[0123] Step 1: Dissolve 1 g of polyvinyl alcohol in deionized water at a mass ratio of 1:9 at 80° C. for more than 2 hours to obtain a polyvinyl alcohol aqueous solution; further, add 2.5 g of polyethylene glycol diacrylate, 0.025 g of a photoinitiator (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropenoate), and 0.025 g of a crosslinker (N,N'-methylenebisacrylamide), and mix well to obtain a hydrogel precursor solution 1;

[0124] Step 2: Take the hydrogel precursor solution 1 prepared in step 1 and squeeze it into a transparent silicone tube through a coaxial needle using a syringe at an extrusion speed of 0.5 mL / s. The transparent silicone tube is irradiated with ultraviolet light using a UVLED annular surface light curing lamp with a wavelength of 265 nm and an intensity of 1000 W / cm 2 After 10 seconds of irradiation, the hydrogel precursor solution 1 can be cross-linked to obtain a hydrogel ureteral stent 1 with an outer diameter of 2.49 mm and an inner diameter of 1.82 mm.

[0125] Preparation of test samples

[0126] (1) Preparation of samples for degradability and compression testing

[0127] Three hydrogel ureteral stents 1 prepared in step 2, each cut into 8 mm in length, were used as sample P25-2 for 28-day degradation test, sample P25-3 for 9-day degradation test, and sample P25-6 for compression test.

[0128] (2) Preparation of samples for microstructure observation

[0129] A section of the hydrogel ureteral stent 1 prepared in step 2 was cut, and the tube wall was split to obtain a test piece exposing the inner and outer surfaces of the stent. The test piece was freeze-dried in liquid nitrogen and sprayed with platinum to obtain sample P25-4 for microstructure observation.

[0130] (3) Preparation of tensile splines

[0131] A hydrogel precursor solution 1 was obtained in the same manner as in step 1 above, and the same ultraviolet light wavelength, light intensity, and irradiation time as in step 2 above were used to mold the hydrogel precursor solution 1 into a national standard type 1 tensile test strip, marked as P25-5.

[0132] (4) Preparation of samples for cross-sectional observation

[0133] The hydrogel ureteral stent 1 prepared in step 2 was cut into a length of 5 mm and used as the sample P25-7 for cross-sectional observation.

[0134] Example 2

[0135] Step 1: Dissolve 1 g of polyvinyl alcohol in deionized water at a mass ratio of 1:9 at 80° C. for more than 2 h to obtain a polyvinyl alcohol aqueous solution; further, add 3 g of polyethylene glycol diacrylate, 0.03 g of a photoinitiator (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropenoate), and 0.03 g of a crosslinker (N,N'-methylenebisacrylamide), and mix well to obtain a hydrogel precursor solution 2;

[0136] Step 2: Take the hydrogel precursor solution 2 prepared in step 1 and squeeze it into a transparent silicone tube through a coaxial needle using a syringe at an extrusion speed of 0.5 mL / s. The transparent silicone tube is irradiated with ultraviolet light using a UVLED annular surface light curing lamp with a wavelength of 265 nm and an intensity of 1500 W / cm 2 After irradiation for 5 seconds, the hydrogel precursor solution 2 can be cross-linked to obtain the hydrogel ureteral stent 2.

[0137] Preparation of test samples

[0138] (1) Preparation of samples for degradability and compression testing

[0139] Two hydrogel ureteral stents 2 prepared in step 2, each cut into a length of 8 mm, were used as sample P30-3 for 9-day degradation test and sample P30-6 for compression test, respectively.

[0140] (2) Preparation of samples for microstructure observation

[0141] A section of the hydrogel ureteral stent 2 prepared in step 2 was cut, and the tube wall was split to obtain a test piece exposing the inner and outer surfaces of the stent. The test piece was freeze-dried in liquid nitrogen and sprayed with platinum to obtain sample P30-4 for microstructure observation.

[0142] (3) Preparation of tensile splines

[0143] The hydrogel precursor solution 2 was obtained in the same manner as in step 1 above, and the same ultraviolet light wavelength, light intensity and irradiation time as in step 2 above were used to shape the hydrogel precursor solution 2 into a national standard type 1 tensile test strip, which was marked as P30-5.

[0144] Comparative Example 1

[0145] Step 1: Dissolve 1 g of polyvinyl alcohol in deionized water at a mass ratio of 1:9 at 80°C for more than 2 h to obtain a polyvinyl alcohol aqueous solution. Further, add 2 g of polyethylene glycol diacrylate, 0.02 g of a photoinitiator (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropenoate), and 0.02 g of a crosslinker (N,N'-methylenebisacrylamide) and mix well to obtain a hydrogel precursor solution 3.

[0146] Step 2: Take the hydrogel precursor solution 3 prepared in step 1 and squeeze it into a transparent silicone tube through a coaxial needle with a syringe at an extrusion speed of 0.5 mL / s. The transparent silicone tube is irradiated with ultraviolet light by a UVLED annular surface light curing lamp with a wavelength of 265 nm and a light intensity of 1000 W / cm 2 After irradiation for 15 seconds, the hydrogel precursor solution 3 can be cross-linked to obtain the hydrogel ureteral stent 3.

[0147] Preparation of test samples

[0148] (1) Preparation of samples for degradability and compression testing

[0149] Two hydrogel ureteral stents 3 prepared in step 2, each cut into 8 mm in length, were used as sample P20-3 for 9-day degradation test and sample P20-6 for compression test, respectively.

[0150] (2) Preparation of samples for microstructure observation

[0151] A section of the hydrogel ureteral stent 3 prepared in step 2 was cut, and the tube wall was split to obtain a test piece exposing the inner and outer surfaces of the stent. The test piece was freeze-dried in liquid nitrogen and sprayed with platinum to obtain sample P20-4 for microstructure observation.

[0152] (3) Preparation of tensile splines

[0153] The hydrogel precursor solution 3 was obtained in the same manner as in step 1 above, and the same ultraviolet light wavelength, light intensity and irradiation time as in step 2 above were used to shape the hydrogel precursor solution 3 into a national standard type 1 tensile test strip, marked as P20-5.

[0154] Test methods and test results

[0155] (1) Degradability test

[0156] (1-1) 28d degradability

[0157] The remaining mass percentage of the sample after degradation was calculated using the following formula (1):

[0158] Remaining mass percentage = Wd / W0×100% (1)

[0159] Furthermore, the degradation rate can be calculated using the following formula (2):

[0160] Degradation rate = 100% - remaining mass percentage = (W0 - Wd) / W0 × 100% (2)

[0161] In formula (1) and formula (2), W0 is the mass of the sample for degradation test before the degradation test, and Wd is the mass of the sample for degradation test after immersion in artificial urine (weighed after taking it out of artificial urine and wiping off the surface moisture).

[0162] The sample P25-2 prepared in Example 1 was immersed in artificial urine at 37°C for 7 days (day represents day), 14 days, 21 days, and 28 days. The samples were taken out at the corresponding time points, and the residual mass percentage was obtained as described above. Figure 2 Shown in.

[0163] like Figure 2 As shown, after sample P25-2 was immersed in artificial urine for 28 days, the remaining mass percentage was 76%, that is, the degradation rate was 24%, indicating that the hydrogel tube had good degradation performance.

[0164] (1-2) 9d degradability

[0165] Samples P25-3, P30-3 and P20-3 were immersed in artificial urine at 37°C for 1 day (day represents day), 2 days, 3 days, 4 days, 5 days, 6 days, 7 days and 9 days respectively. The samples were taken out at the corresponding time points and the residual mass percentage was obtained as described above. Figure 3 Shown in.

[0166] from Figure 3 It can be seen that with the increase of PVA content, the remaining mass percentage decreases and the degradation rate of the hydrogel material increases.

[0167] (1-3) In vivo degradability

[0168] To simulate the degradability of the ureteral stent in the human body, a 5 mm long hydrogel ureteral stent 1 obtained in Example 1 was taken and embedded subcutaneously in mice. Specifically, the skin at the belly of the mouse was cut open, the hydrogel ureteral stent was embedded, and then the skin was sutured. The mice were fed normally for 28 days and then killed. After the skin was cut open at the same location, no hydrogel material was found, indicating that it had been completely absorbed, proving that the hydrogel ureteral stent can be completely degraded in the body. In addition, no inflammation was detected at the location where the hydrogel ureteral stent was embedded after the cut open, proving that the degradation of the hydrogel ureteral stent in the body did not cause inflammation.

[0169] (2) Microstructure

[0170] The microstructure of each of the samples P25-4, P30-4 and P20-4 as a portion of the outer surface of the bracket was observed using a field emission environmental scanning electron microscope at a magnification of 3000 times. Figure 4 Shown in.

[0171] like Figure 4 As shown in the figure, the network arrangement shown in the figure is a cross-linked network structure of polyethylene glycol diacrylate. As the content of polyethylene glycol diacrylate in the hydrogel material increases, the network arrangement of the hydrogel material becomes more orderly.

[0172] (3) Mechanical properties test

[0173] The mechanical properties are tested by an electronic universal testing machine.

[0174] (3-1) Tensile performance test

[0175] The tensile properties of samples P25-5, P30-5 and P20-5 were tested using an electronic universal testing machine at a tensile speed of 5 mm / min. Figure 5 shown.

[0176] like Figure 5 As shown, the tensile strength at break of P25-5 is 210 kPa, the tensile strength at break of P30-5 is 460 kPa, and the tensile strength at break of P20-5 is 8 kPa.

[0177] (3-2) Compression performance test

[0178] Samples P25-6, P30-6 and P20-6 were used respectively. The compression performance was tested using an electronic universal testing machine at a compression speed of 2mm / min. The test results are as follows: Figure 6 shown.

[0179] like Figure 6 As shown, when the samples were compressed to 80% of their initial height, the compressive strength of sample P20-6 was 90 kPa, the compressive strength of sample P25-6 was 245 kPa, and the compressive strength of sample P30-6 was 336 kPa.

[0180] from Figure 5 and Figure 6 It can be seen that with the increase of the content of polyethylene glycol diacrylate, the tensile strength and compressive strength of the hydrogel material are both increased.

[0181] (4) Macrostructure

[0182] Figure 7 This is a cross-sectional view of the cross-sectional observation sample P25-7 obtained by backlighting using a contact angle measuring instrument using the illumination and photographing functions of the measuring instrument. Figure 7 It can be seen that the cross-section is a clear concentric tube shape with an outer diameter of 2.49 mm and an inner diameter of 1.82 mm, which meets the size and structure requirements of the ureteral stent and has a clear and stable structure.

[0183] Industrial applicability

[0184] The degradable ureteral stent of the present invention can be used in the field of medical devices, and the preparation method of the degradable ureteral stent of the present invention can be used for batch production of the degradable ureteral stent.

Claims

1. A degradable ureteral stent, characterized in that: The degradable ureteral stent comprises a double network structure hydrogel, which comprises a network structure formed by a polyethylene glycol diacrylate cross-linked polymer and a network structure formed by polyvinyl alcohol, wherein the polyethylene glycol diacrylate cross-linked polymer is formed by cross-linking polyethylene glycol diacrylate and an optional cross-linking agent, and the network structure formed by polyvinyl alcohol is a network structure formed by polyvinyl alcohol molecular chains entangled with each other and optionally entangled with the network structure formed by the polyethylene glycol diacrylate cross-linked polymer.

2. The degradable ureteral stent according to claim 1, characterized in that: In the double network structure hydrogel, the mass ratio of the polyvinyl alcohol to the polyethylene glycol diacrylate cross-linked polymer is (0.20-0.45):1; the weight average molecular weight of the polyvinyl alcohol is 70,000-130,000, preferably 85,000-124,000; the weight average molecular weight of the polyethylene glycol diacrylate is 900-7,000, preferably 1,000-6,000.

3. The degradable ureteral stent according to claim 1 or 2, characterized in that: The water content is 60 mass % to 75 mass % relative to the total mass of the double network structure hydrogel.

4. The degradable ureteral stent according to any one of claims 1 to 3, characterized in that: The cross-linking agent is N,N'-methylenebisacrylamide and / or hydroxyethyl methacrylate; the mass ratio of the polyethylene glycol diacrylate to the cross-linking agent is 100:(0-6), preferably 100:(1-5).

5. The degradable ureteral stent according to any one of claims 1 to 4, characterized in that: The double network structure hydrogel also contains additives; relative to the total mass of the double network structure hydrogel, the content of the additive is less than 5 mass%, preferably less than 3 mass%; the additive is one or more selected from antibacterial agents, medical developers, plasticizers, lubricants and dyes.

6. The degradable ureteral stent according to any one of claims 1 to 5, characterized in that: The degradable ureteral stent is in the shape of a circular tube; the outer diameter of the degradable ureteral stent is 1.4 to 3.2 mm, and the inner diameter is 1.0 to 2.0 mm.

7. A method for preparing a degradable ureteral stent according to any one of claims 1 to 6, characterized in that: The following steps are involved: Step 1: adding polyethylene glycol diacrylate, a photoinitiator, and optionally the crosslinking agent and the additive into a polyvinyl alcohol aqueous solution, and mixing them uniformly to prepare a hydrogel precursor solution; Step 2: The hydrogel precursor solution prepared in step 1 is coaxially extruded into an ultraviolet light irradiation environment to obtain the degradable ureteral stent.

8. The method for preparing a degradable ureteral stent according to claim 7, characterized in that: In the polyvinyl alcohol aqueous solution, the mass ratio of the polyvinyl alcohol to the water is 0.7:9.3 to 3:7, preferably 1:9 to 2:8; the preparation method also includes dissolving polyvinyl alcohol in water under heating conditions to obtain the polyvinyl alcohol aqueous solution; the heating conditions are a heating temperature of 75°C to 95°C, preferably a heating temperature of 80°C to 90°C.

9. The method for preparing a degradable ureteral stent according to claim 7 or 8, characterized in that: The photoinitiator is one or more selected from 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropenone, 1-hydroxycyclohexyl phenyl ketone, 2-isopropylthioxanthone, and 2,4,6-trimethylbenzoyl-diphenylphosphine oxide; in the step 1, the ratio of the added amounts of the polyethylene glycol diacrylate, the photoinitiator, and the cross-linking agent is 100:(0.5-6):(0-6) by mass ratio, preferably 100:(1-5):(1-5).

10. The method for preparing a degradable ureteral stent according to any one of claims 7 to 9, characterized in that: In step 2, the coaxial extrusion is performed by coaxial needle extrusion; the hydrogel precursor solution is extruded into the light-transmitting silicone tube through the coaxial needle, and the light-transmitting silicone tube is irradiated by ultraviolet light; the wavelength of the ultraviolet light is 253nm to 385nm, and the intensity of the ultraviolet light is 800 to 2000W / cm 2 , the UV irradiation time is 60s to 4s.

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