A hydrophilic lubricous analgesic rubber urinary catheter and a method of making the same

Abstract

This invention provides a hydrophilic, lubricated, and analgesic rubber urinary catheter and its preparation method, relating to the field of medical device technology. The catheter surface is sequentially coated with an adhesion layer, a pH-temperature responsive analgesic layer, and a hydrophilic layer. The pH-temperature responsive analgesic layer is a Janus fiber felt, with a pH-sensitive polymer and an analgesic drug on one side and a temperature-sensitive polymer and an analgesic drug on the other side. The analgesic layer of the catheter provided by this invention employs a Janus fiber structure and simultaneously loads both a pH-sensitive polymer and a temperature-sensitive polymer. This structure can accurately sense pathological changes in the urethral microenvironment and actively and synergistically regulate the release behavior of the analgesic drug accordingly, effectively relieving catheter-related bladder irritation syndrome (CRBD).

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and in particular to a hydrophilic, lubricated, analgesic rubber catheter and its preparation method. Background Technology

[0002] Indwelling urinary catheters are a routine medical procedure for managing urination in surgical patients, critically ill patients, and long-term bedridden patients. However, as an invasive procedure, it is accompanied by significant clinical challenges. During catheterization, the mechanical friction between the catheter and the urethral mucosa can easily cause pain, discomfort, and even mucosal damage. During long-term indwelling, foreign body irritation and pressure from the balloon on the bladder trigone often lead to catheter-related bladder irritation (CRBD) in 50%-90% of patients, manifested as severe urinary urgency, frequency, suprapubic pain, and a burning sensation at the urethral orifice, seriously affecting the patient's recovery quality and comfort, and even inducing abnormal heart rate and blood pressure. To alleviate these problems, clinical practice routinely applies a local anesthetic gel such as tetracaine hydrochloride or lidocaine to the outside of the catheter before insertion. While this method has some effect, it has significant limitations: First, it is cumbersome to operate and relies on the experience of medical staff; second, the effect is short-lived, with the analgesic effect of a single application lasting only 1-3 hours, which cannot cover the indwelling period of several days or even weeks; third, the drug is only present in the initial segment of the outer wall of the catheter, and as the catheter is inserted deeper, the lubrication and analgesia effects decrease sharply, providing insufficient protection for the urethra throughout the procedure; finally, this is a passive and indiscriminate drug release, which cannot be intelligently adjusted according to individual patient differences or pathological changes such as infection and inflammation that may occur during the indwelling period.

[0003] In recent years, researchers have focused on developing functional catheter coatings with lubricating or sustained-release properties. For example, water-based lubrication is achieved by coating the catheter surface with hydrophilic polymers (such as polyvinylpyrrolidone, PVP), or sustained release is achieved by dispersing local anesthetics in a polymer matrix. However, existing technologies are mostly simple physical mixtures or laminates with single functions, exhibiting the following bottlenecks: First, lubrication and analgesia are often independent, failing to synergistically enhance each other; second, drug release largely relies on simple diffusion mechanisms, exhibiting a constant rate or a pattern of initially rapid release followed by slower release, unable to respond to changes in the internal environment. When a patient experiences a urinary tract infection, the pH of the infected area rises from the normal slightly acidic level (approximately pH 6.5) to an alkaline level (pH 7.5-8.5), possibly accompanied by an increase in tissue temperature. However, traditional coatings cannot sense and respond to these crucial pathological signals, thus failing to increase the drug delivery intensity at the moment when the patient most needs analgesia, resulting in insufficient efficacy under pathological conditions.

[0004] Therefore, there is an urgent clinical need for a new type of catheter coating technology that can not only provide long-lasting lubrication and analgesia, but also intelligently sense pathological changes in the urethral microenvironment and actively and precisely adjust the release behavior of therapeutic drugs accordingly. This would achieve a leap from "passive sustained release" to "active response," thereby providing an adaptive, integrated, and comfortable medical solution throughout the entire indwelling period, fundamentally reducing the incidence of CRBD and improving patient compliance and recovery experience. Summary of the Invention

[0005] The purpose of this invention is to provide a hydrophilic, lubricating, and analgesic rubber catheter and its preparation method. This invention adopts a Janus fiber structure and simultaneously loads a pH-sensitive polymer and a temperature-sensitive polymer. This structure can accurately sense pathological changes in the urethral microenvironment (such as pH increase caused by infection or body temperature rise caused by inflammation) and thereby actively and synergistically regulate the release behavior of analgesic drugs, which can effectively relieve catheter-related bladder irritation syndrome (CRBD).

[0006] To achieve the above objectives, the present invention adopts the following technical solution: The present invention provides a hydrophilic lubricating and analgesic rubber catheter, wherein the surface of the catheter is sequentially coated with an adhesion layer, a pH-temperature responsive analgesic layer and a hydrophilic layer; The pH-temperature responsive analgesic layer is a Janus fiber felt, with a pH-sensitive polymer and analgesic drug on one side and a temperature-sensitive polymer and analgesic drug on the other side.

[0007] Furthermore, based on the above technical solution, the adhesion layer contains polyurethane, specifically water-based polyurethane; And / or, the hydrophilic layer contains a hydrophilic compound, including one or more of polyvinylpyrrolidone, polyethylene glycol, and hyaluronic acid; And / or, the pH-sensitive polymer includes one or more of polyacrylic acid, acrylic acid copolymers, crosslinked polyacrylic acid, and poly(N,N-dimethylaminoethyl methacrylate); And / or, the temperature-sensitive polymer includes one or more of poly(N-isopropylacrylamide), polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, and polyvinyl methyl ether; And / or, the analgesic includes one or more of tetracaine hydrochloride, lidocaine hydrochloride, and oxybuprocaine hydrochloride.

[0008] Furthermore, based on the above technical solution, the thickness of the adhesion layer is 3-10 μm, the thickness of the pH-temperature responsive analgesic layer is 30-80 μm, and the thickness of the hydrophilic layer is 1-5 μm.

[0009] The present invention also provides a method for preparing the hydrophilic lubricating and analgesic rubber urinary catheter as described above, comprising the following steps: S1: Perform surface pretreatment on the rubber catheter, and then coat the surface of the pretreated rubber catheter with an adhesion layer to obtain the first catheter; S2: Mix the pH-sensitive polymer and the analgesic drug in a solvent to obtain solution A; mix the temperature-sensitive polymer and the analgesic drug in a solvent to obtain solution B; S3: Inject liquid A and liquid B into the electrospinning equipment for spinning to obtain Janus fiber felt. Then, heat-press the Janus fiber felt onto the surface of the first catheter to obtain the second catheter. S4: Fix the second catheter onto the spin coating device, and drop a hydrophilic layer solution onto its surface until a hydrophilic film is formed to obtain the third catheter; S5: The third catheter is cured by gradient heating to obtain a hydrophilic, lubricated, and analgesic rubber catheter.

[0010] Furthermore, based on the above technical solution, in step S1, the surface pretreatment includes the following steps: Low-temperature oxygen plasma treatment of rubber catheters is performed at a power of 60-90W for 40-70s to improve the surface activity and coating adhesion of the rubber catheters. And / or, applying the adhesion layer includes the following steps: Polyurethane is dissolved in deionized water or ethanol solution to prepare a coating solution. The pretreated rubber catheter is immersed in the coating solution and dried to obtain the first catheter. The mass percentage concentration of the coating solution is 5-10%. The soaking time is 30-60 seconds, the drying temperature is 60-80℃, and the drying time is 1-2 hours.

[0011] Furthermore, based on the above technical solution, in step S2, the solvent includes deionized water or an ethanol solution; And / or, the mass ratio of pH-sensitive polymer to analgesic drug is 1:5 to 1:10; And / or, the mass percentage concentration of solution A is 8-12%; And / or, the mass ratio of the thermosensitive polymer to the analgesic drug is 1:4 to 1:6; And / or, the mass percentage concentration of solution B is 10-15%; And / or, the total mass of liquid A and liquid B is the same.

[0012] Furthermore, based on the above technical solution, the technical parameters of the electrospinning equipment include: The spinning voltage is 15-25 kV, the receiving device is a roller covered with aluminum foil, the distance between the receiving device and the nozzle is 15-25 cm, the temperature is 22-28℃, the humidity is 35-45%, the solution propulsion rate of liquid A and liquid B is 0.8-1.5 mL / h, and the rotation speed of the receiving device is 100-500 rpm. And / or, the hot pressing temperature is 80-100℃, the pressure is 0.1-0.5 MPa, and the hot pressing time is 1-2 min.

[0013] Furthermore, based on the above technical solution, in step S4, the hydrophilic layer solution is a mixed solution of deionized water and ethanol with a volume ratio of 7-9:1, in which the hydrophilic compound is placed. And / or, the mass percentage concentration of the hydrophilic layer solution is 2-4%.

[0014] Furthermore, based on the above technical solution, the spin coating device rotates at 300-500 rpm. The prepared hydrophilic layer solution is added slowly and uniformly along the axial direction of the catheter using a pipette to ensure that the solution can instantly wet and cover the entire surface of the fiber felt. Then, the rotation speed is increased to 800-1000 rpm and maintained for 30-60 seconds, so that the solution remaining on the surface of the catheter spreads evenly on the tube wall and quickly levels to form a film.

[0015] Furthermore, based on the above technical solution, the third catheter is placed in an oven at 60-80℃ and cured for 20-30 minutes, then the temperature is raised to 80-100℃ and cured for another 1-2 hours.

[0016] The present invention provides a hydrophilic, lubricating, and analgesic rubber urinary catheter and its preparation method, the beneficial effects of which include at least the following: 1. The hydrophilic lubricating analgesic rubber catheter provided by the present invention has an analgesic layer with a Janus fiber structure, and is loaded with a pH-sensitive polymer and a temperature-sensitive polymer. This structure can accurately sense pathological changes in the urethral microenvironment (such as pH increase caused by infection or body temperature rise caused by inflammation), and accordingly actively and synergistically regulate the release behavior of analgesic drugs, which can effectively relieve catheter-related bladder irritation syndrome (CRBD).

[0017] 2. This invention abandons the traditional impregnation method of simple physical mixing and innovatively uses parallel electrospinning technology to prepare Janus fiber felt. This process enables the prepared catheter to achieve the synergistic release of pH-responsive and temperature-responsive units, which can ensure long-term efficacy while effectively responding to sudden pain stimulation and effectively relieving catheter-related bladder irritation syndrome (CRBD). Detailed Implementation

[0018] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions in the embodiments of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Those skilled in the art should understand that the embodiments described are merely illustrative of the invention and should not be considered as specific limitations thereof. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention. Process parameters not specifically specified in the following embodiments are generally performed under conventional conditions.

[0019] The endpoints and any values ​​of the ranges disclosed in this invention are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this invention.

[0020] According to a first aspect of the present invention, a hydrophilic lubricating and analgesic rubber catheter is provided, wherein the surface of the catheter is sequentially coated with an adhesion layer, a pH-temperature responsive analgesic layer and a hydrophilic layer; The pH-temperature responsive analgesic layer is made of Janus fiber felt (Janus fiber felt refers to two sides of the same fiber felt that have drastically different physical or chemical properties. This asymmetry enables it to achieve directional delivery or intelligent response functions). One side of the Janus fiber felt contains a pH-sensitive polymer and analgesic drug, while the other side contains a temperature-sensitive polymer and analgesic drug.

[0021] Specifically, when bacterial infection (such as urinary tract infection) occurs in the indwelling catheter area, bacterial metabolites (such as urease breaking down urea to produce ammonia) cause a significant increase in the local microenvironment pH, reaching 7.5-8.5 or even higher. Under these alkaline conditions, this invention, by selecting a pH-sensitive polymer, can form a more loose and porous gel network through pH changes, thereby providing more and wider channels for drug molecule diffusion, significantly accelerating the drug release rate, and achieving targeted and enhanced analgesia at the site of infection / inflammation. Furthermore, when a patient experiences a local or systemic increase in body temperature (e.g., >37°C) due to postoperative reactions or infection, the thermosensitive polymer used in this invention possesses a unique "low critical solution temperature" (LCST). When the ambient temperature is below the LCST, the polymer molecular chains are tightly bound to water molecules through hydrogen bonds, exhibiting a relaxed hydrophilic state and providing basic hydrophilic lubrication. When the ambient temperature is above the LCST, hydrophobic interactions between polymer molecular chains become dominant, hydrogen bonds are broken, and the polymer chains undergo dehydration and contraction, changing from a hydrophilic relaxed state to a hydrophobic contracted state. This alters the network density and pore size of the hydrophilic layer, creating additional diffusion pathways or driving forces for drug molecules from the inner analgesic layer. In conjunction with pH response, this further regulates release behavior.

[0022] As an optional embodiment of the present invention, the adhesion layer contains polyurethane, specifically waterborne polyurethane (model U502, Oubaodi). The hydrophilic layer contains hydrophilic compounds, including one or more of polyvinylpyrrolidone, polyethylene glycol, and hyaluronic acid.

[0023] As an optional embodiment of the present invention, the pH-sensitive polymer includes one or more of polyacrylic acid, acrylic acid copolymers (such as poly(acrylic acid-co-methacrylic acid), wherein the molar ratio of acrylic acid to methacrylic acid is between 2:8 and 4:6), crosslinked polyacrylic acid (such as carbomer), and poly(N,N-dimethylaminoethyl methacrylate); Specifically, polyacrylic acid compounds such as polyacrylic acid, acrylic acid copolymers, and cross-linked polyacrylic acid contain carboxyl groups (-COOH) in their molecular chains. When the ambient pH increases, they ionize into -COO⁻. The charge repulsion causes the polymer chains to swell, increasing the network pores. For infectious inflammatory sites in the urethra (where the pH is usually greater than 7.4), the swelling of the coating can accelerate the release of analgesic drugs, achieving targeted and enhanced analgesia. Poly(N,N-dimethylaminoethyl methacrylate) contains tertiary amine groups, which protonate when the pH decreases, changing from hydrophobic to hydrophilic, resulting in swelling or dissolution. Its pH response can be adjusted through copolymerization to adapt to different physiological or pathological microenvironments.

[0024] The thermosensitive polymer includes one or more of poly(N-isopropylacrylamide), polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer (PEO-PPO-PEO, such as poloxamer), and polyvinyl methyl ether.

[0025] Specifically, poly(N-isopropylacrylamide)PNIPAM has a minimum critical solution temperature (LCST, approximately 32-34°C). When the temperature is higher than the LCST, the polymer chains dehydrate and shrink, increasing hydrophobicity. When the patient's body temperature rises (e.g., >37°C), the phase transition dynamically enhances the hydrophilicity of the coating surface, reduces the coefficient of friction, and improves comfort during fever.

[0026] The polyoxypropylene (PPO) segment in the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer is a thermosensitive hydrophobic segment. When the temperature rises above a critical value, the PPO segment dehydrates and aggregates, initiating a sol-gel transition. It can be used to construct thermosensitive gel coatings. At body temperature, a lubricating gel layer is formed, which can encapsulate drugs, achieving temperature-controlled sustained release.

[0027] Polyvinyl methyl ether has LCST properties (approximately 34-35°C), and its temperature response behavior is similar to that of PNIPAM.

[0028] The analgesic drugs include one or more of tetracaine hydrochloride, lidocaine hydrochloride, and oxybuprocaine hydrochloride.

[0029] As an optional embodiment of the present invention, the thickness of the adhesion layer is 3-10 μm, the thickness of the pH-temperature responsive analgesic layer is 30-80 μm, and the thickness of the hydrophilic layer is 1-5 μm.

[0030] According to a second aspect of the present invention, a method for preparing the hydrophilic lubricating and analgesic rubber urinary catheter as described above is provided, comprising the following steps: S1: Perform surface pretreatment on the rubber catheter, and then coat the surface of the pretreated rubber catheter with an adhesion layer to obtain the first catheter; S2: Mix the pH-sensitive polymer and the analgesic drug in a solvent to obtain solution A; mix the temperature-sensitive polymer and the analgesic drug in a solvent to obtain solution B; S3: Inject liquid A and liquid B into the electrospinning equipment for spinning to obtain Janus fiber felt. Then, heat-press the Janus fiber felt onto the surface of the first catheter to obtain the second catheter. S4: Fix the second catheter onto the spin coating device, and drop a hydrophilic layer solution onto its surface until a hydrophilic film is formed to obtain the third catheter; S5: The third catheter is cured by gradient heating to obtain a hydrophilic, lubricated, and analgesic rubber catheter.

[0031] In an optional embodiment of the present invention, step S1, the surface pretreatment includes the following steps: The rubber catheter is subjected to low-temperature oxygen plasma treatment with a power of 60-90W (e.g., 65W, 70W, 75W, 80W, 85W) for 40-70s (e.g., 50s, 60s, 65s, etc.) to improve the surface activity and coating adhesion of the rubber catheter.

[0032] Specifically, if the power is too low, the activation will be insufficient and the coating will easily peel off; if it is too high, it may damage the surface structure of the latex.

[0033] As an optional embodiment of the present invention, coating the adhesion layer includes the following steps: Polyurethane is dissolved in deionized water or ethanol solution to prepare a coating solution. The pretreated rubber catheter is immersed in the coating solution and dried to obtain the first catheter. The mass percentage concentration of the coating solution is 5-10% (e.g., 6%, 7%, 8%, 9%, etc.). The soaking time is 30-60s (35s, 40s, 45s, 55s, etc.), the drying temperature is 60-80℃ (e.g., 65℃, 70℃, 75℃, etc.), and the time is 1-2h (e.g., 1.2h, 1.5h, 1.7h, etc.).

[0034] In an optional embodiment of the present invention, in step S2, the solvent includes deionized water or an ethanol solution; the ethanol solution is a mixture of ethanol and deionized water with a volume ratio of 7:3. The mass ratio of pH-sensitive polymer to analgesic drug is 1:5 to 1:10 (e.g., 1:6, 1:7, 1:8, 1:9, 1:10, etc.). Specifically, on the pH-responsive side of the Janus fiber felt, a high load of analgesic drug is added to ensure sufficient analgesic drug reserves during long-term retention. This also ensures that the pH-sensitive polymer can form a continuous pH-responsive network. When the pH increases, the mechanical force generated by polymer swelling can efficiently act on the large amount of drug encapsulated within, achieving rapid drug release to cope with infection stimulation. If there is too little polymer (e.g., a pH-sensitive polymer to analgesic drug mass ratio of 1:12), the polymer cannot form a continuous network, the mechanical force generated by swelling is insufficient to effectively promote drug release, and the drug is prone to sudden release. Furthermore, the coating has poor mechanical strength and is easily damaged. Conversely, if there is too much polymer (e.g., a pH-sensitive polymer to analgesic drug mass ratio of 1:4), the drug is encapsulated in an excessively thick polymer matrix. Even if swelling occurs, the release rate is too slow to meet the demand for rapid analgesia. Additionally, an excessively thick coating significantly prolongs the time for stimulation signals (pH changes) to penetrate and for the internal drug to diffuse out.

[0035] The mass percentage concentration of solution A is 8-12% (e.g., 9%, 10%, 11%, etc.). The mass ratio of thermosensitive polymer to analgesic drug is 1:4 to 1:6 (e.g., 1:4.5, 1:5, 1:5.5, etc.). Specifically, on the temperature-responsive side of Janus fiber mat, a certain content and cross-linking density of thermosensitive polymer are required to achieve a significant hydrophilic-hydrophobic phase transition when the temperature crosses the LCST, thereby effectively opening and closing drug diffusion channels. If there is too little polymer (e.g., the mass ratio of thermosensitive polymer to analgesic drug is 1:8), the phase transition of the thermosensitive polymer will be insignificant, failing to effectively regulate drug diffusion and losing its temperature-responsive function. If there is too much polymer (e.g., the mass ratio of thermosensitive polymer to analgesic drug is 1:3), the overly dense polymer network will hinder drug diffusion, resulting in limited release even under heating conditions.

[0036] The mass percentage concentration of solution B is 10-15% (e.g., 11%, 12%, 13%, 14%, etc.). The total mass of solution A and solution B is the same.

[0037] Specifically, under the premise that the total mass of solutions A and B is the same, by limiting the drug loading on the pH-responsive side to be greater than that on the temperature-responsive side, a functionally complementary and synergistically enhanced intelligent cascade release system is constructed. Its core relationship lies in: through differentiated drug loading strategies, both sides can perform analgesic tasks with different priorities and intensities based on the type and intensity of the stimulus signal. Specifically: In the early stages of infection, the temperature within the patient's urethra may be slightly elevated. The temperature-responsive side releases the drug first, providing immediate relief for early discomfort and paving the way for the subsequent release of a large amount of drug from the pH-responsive side. As the infection worsens and causes a significant increase in the pH within the patient's urethra, the pH-responsive side is activated. The micromechanical force generated by its swelling not only releases its own drug but also synergistically compresses the structure of the temperature-responsive side, further releasing the drug there, thus achieving a synergistic acceleration of drug release. This response process, from "temperature-sensitive early warning and regulation" to "pH-enhanced therapy," provided by this invention, can dynamically match drug release with the progress of clinical needs, thereby maximizing treatment efficiency and reducing drug waste while extending the duration of action.

[0038] As an optional embodiment of the present invention, the technical parameters of the electrospinning equipment (model ET-2535X, manufactured by Beijing Yongkang Leyue) include: The spinning voltage is 15-25 kV (e.g., 17kV, 20kV, 23kV, etc.), the receiving device is a roller covered with aluminum foil, the distance between the receiving device and the nozzle is 15-25 cm (e.g., 17cm, 20cm, 23cm, etc.), the temperature is 22-28℃ (e.g., 23℃, 25℃, 27℃, etc.), the humidity is 35-45% (e.g., 38%, 40%, 42%, etc.), the solution propulsion rate of both solution A and solution B is 0.8-1.5 mL / h (e.g., 1mL / h, 1.2mL / h, 1.3mL / h, 1.4mL / h, etc.), the rotation speed of the receiving device is 100-500 rpm (e.g., 200rpm, 300rpm, 400rpm, 450rpm, etc.), and the spinning time can be controlled according to actual needs, without specific limitations here.

[0039] Specifically, liquids A and B are injected into two independent medical syringes in the electrospinning equipment and installed in parallel spinning nozzles (two capillaries side by side with a tip spacing of about 0.5-1.0 mm). The nozzles are connected to the high-voltage positive electrode, and the receiving device is connected to the negative electrode or grounded.

[0040] Furthermore, if the solution propagation rates of liquid A and liquid B are inconsistent, it can easily lead to asymmetry on both sides of the Janus fiber, or even one side being wrapped by the other side, thus losing its "two-sidedness".

[0041] As an optional embodiment of the present invention, the hot-pressing temperature is 80-100℃ (e.g., 85℃, 90℃, 95℃, etc.), the applied pressure is 0.1-0.5 MPa (e.g., 0.2MPa, 0.3MPa, 0.4MPa, etc.), and the hot-pressing time is 1-2 min (e.g., 1.2 min, 1.5 min, 1.7 min, etc.). Without damaging the fiber structure, the fiber can be slightly melted at this temperature, causing the polymer to soften, diffuse and entangle with each other, and firmly bonded to the surface of the first catheter.

[0042] Typically, and non-limitingly, the specific operation of hot pressing includes: fixing the first catheter in a heat-resistant, flat silicone V-groove mold to ensure that the catheter segment to be bonded is stable and fully exposed; peeling the prepared Janus fiber felt off the aluminum foil receiving device, precisely cutting it according to the circumference of the catheter and the required length, and then carefully wrapping and bonding the fiber felt to the target area of ​​the catheter; furthermore, to avoid adhesion caused by direct contact with the hot pressing head, a layer of high-temperature resistant, smooth, and non-adhesive polyimide film needs to be covered on the outside of the fiber felt; hot pressing is performed using a hot press; after hot pressing, cooling is performed; finally, the polyimide film is removed, and the Janus fiber felt is firmly bonded to the surface of the first catheter, obtaining the second catheter.

[0043] It should be further explained that the phase transition of thermosensitive polymers (taking PNIPAM as an example) is a temperature-driven, reversible hydrophilic-hydrophobic transition in an aqueous environment. The mechanism is as follows: when the temperature is below the LCST, the PNIPAM molecular chains are tightly bound to water molecules through hydrogen bonds and expand and dissolve (hydrophilic state); when the temperature is above the LCST, the hydrogen bonds are broken, and the hydrophobic effect inside the molecular chain becomes dominant, causing the chain to curl up and dehydrate and aggregate (hydrophobic state). In a dry air environment, the movement of PNIPAM chain segments is only constrained by its glass transition temperature (Tg). Therefore, when the hot pressing temperature (80-100℃) is close to or slightly higher than its Tg, the polymer chain segments gain enough energy to begin to move, and the material changes from the glassy state to the elastic state or viscous flow state, thereby causing softening, diffusion and entanglement at the fiber contact points.

[0044] As an optional embodiment of the present invention, in step S4, the hydrophilic layer solution is a mixed solution of deionized water and ethanol with a volume ratio of 7-9:1, in which the hydrophilic compound is placed. The mass percentage concentration of the hydrophilic layer solution is 2-4% (e.g., 2.5%, 3%, 3.5%, etc.). Low concentrations of hydrophilic layer solution can achieve extremely thin hydrophilic layer thickness (1-5 μm). If the concentration is too high (e.g., 6%), the solution is viscous, and the film layer after spin coating is too thick, which will seriously hinder drug diffusion and cause the smart response to fail. If the concentration is too low (e.g., <1%), a continuous and complete hydrophilic film may not be formed, and it will not play a protective role.

[0045] As an optional embodiment of the present invention, the spin coating device rotates at 300-500 rpm (e.g., 350 rpm, 400 rpm, 450 rpm, etc.). The prepared hydrophilic layer solution is added dropwise along the axial direction of the catheter using a pipette at a uniform speed and slowly to ensure that the solution can instantly wet and cover the entire surface of the fiber felt. Then, the rotation speed is quickly increased to 800-1000 rpm (850 rpm, 900 rpm, 950 rpm, etc.) and maintained for 30-60 seconds (e.g., 30 seconds, 40 seconds, 50 seconds, 55 seconds, etc.). Under the strong centrifugal force generated by the high-speed rotation, the excess solution is thrown off, and the solution remaining on the surface spreads evenly on the tube wall and quickly levels to form a film.

[0046] Specifically, one end of the second catheter is tightly connected to the shaft of the spin coating device (a miniature DC motor, model WST42GHM), while the other end is gently supported by a freely rotatable pin or bearing, ensuring that the catheter can rotate at high speed and smoothly along its long axis, and that the suspended section will not swing violently due to centrifugal force.

[0047] In an optional embodiment of the present invention, step S5, the gradient temperature curing, includes: placing the third catheter in an oven at 60-80℃ (e.g., 65℃, 70℃, 75℃, etc.) and curing for 20-30 minutes (e.g., 22 minutes, 25 minutes, 27 minutes, etc.). This stage mainly removes excess moisture and solvent. Subsequently, the temperature is raised to 80-100℃ (e.g., 85℃, 90℃, 95℃, etc.) and curing continues for 1-2 hours (e.g., 1.2 hours, 1.5 hours, 1.7 hours, etc.). The gradient temperature curing method used in this invention is to avoid rapid evaporation of moisture on or inside the hydrophilic layer, which can generate bubbles.

[0048] The present invention will be further described in detail below with reference to specific embodiments and comparative examples. Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments used, unless otherwise specified, are all commercially available products.

[0049] Example 1

[0050] This embodiment provides a hydrophilic lubricating and analgesic rubber catheter, the surface of which is sequentially coated with an adhesion layer (thickness of about 8 μm), a pH-temperature responsive analgesic layer (thickness of about 50 μm), and a hydrophilic layer (thickness of about 3 μm). The pH-temperature responsive analgesic layer is a Janus fiber felt, with one side of the Janus fiber felt being polyacrylic acid and tetracaine hydrochloride, and the other side being poly(N-isopropylacrylamide) and tetracaine hydrochloride.

[0051] This embodiment also provides a method for preparing the hydrophilic lubricating and analgesic rubber urinary catheter as described above, comprising the following steps: S1: The rubber catheter is subjected to low-temperature oxygen plasma treatment at a power of 70W for 50s. The pretreated rubber catheter is then immersed in a 5% (w / w) coating solution (water-based polyurethane (model U502, Oubaodi) dissolved in deionized water) for 60s, and then dried at 80℃ for 1h to obtain the first catheter.

[0052] S2: Mix polyacrylic acid and tetracaine hydrochloride in an ethanol solution at a mass ratio of 1:8 to obtain solution A (mass percentage concentration of 10%); mix poly(N-isopropylacrylamide) and tetracaine hydrochloride in an ethanol solution (volume ratio of 7:3 of ethanol and deionized water) at a mass ratio of 1:4 to obtain solution B (mass percentage concentration of 10%). The total mass of liquid A and liquid B is the same.

[0053] S3: Inject solutions A and B into two independent medical syringes in the electrospinning equipment (model ET-2535X, manufacturer: Beijing Yongkang Leyue), respectively, and install them into parallel spinning nozzles (two capillaries side-by-side, tip-to-tip distance approximately 1.0mm). Connect the nozzles to the high-voltage positive electrode and the receiving device to the negative electrode; set the technical parameters of the electrospinning equipment: The spinning voltage is 20 kV, the receiving device is a roller covered with aluminum foil, the distance between the receiving device and the nozzle is 20 cm, the temperature is 25℃, the humidity is 40%, the solution propulsion rate of liquid A and liquid B is 1 mL / h, and the rotation speed of the receiving device is 100 rpm. After turning on the equipment and spinning for 4 hours, Janus fiber felt is obtained. The first catheter is fixed in a silicone V-groove mold to ensure that the first catheter segment to be bonded is stable and fully exposed. The prepared Janus fiber felt, which has been peeled off from the aluminum foil receiving device, is precisely cut according to the circumference of the catheter and the required length (circumference of 14 mm, test length of 5 cm). Then, the fiber felt is carefully wrapped and bonded to the surface of the first catheter. Furthermore, to avoid adhesion caused by direct contact with the hot press head, a layer of high-temperature resistant, smooth, and non-adhesive polyimide film is covered on the outside of the fiber felt. Hot pressing is performed using a hot press at a temperature of 95°C, a pressure of 0.3 MPa, and a pressing time of 1 min. After hot pressing, the material is cooled to room temperature and the polyimide film is removed. The Janus fiber felt is now firmly bonded to the surface of the first catheter, resulting in the second catheter.

[0054] S4: Connect one end of the second catheter tightly to the shaft of the spin coating device (micro DC motor, model WST42GHM), and gently support the other end with a freely rotatable pin to ensure that the tube can rotate at high speed and smoothly along its long axis, and that the suspended section will not be violently shaken due to centrifugal force; the spin coating device rotates at 400 rpm. Use a pipette to add the prepared hydrophilic layer solution at a uniform and slow speed along the axial direction of the catheter, ensuring that the solution can instantly wet and cover the entire surface of the fiber felt. Then quickly increase the speed to 1000 rpm and maintain it for 30 seconds. Under the strong centrifugal force generated by the high-speed rotation, the excess solution is thrown off, and the solution remaining on the surface spreads evenly on the tube wall and quickly flows and forms a film to obtain the third catheter; The hydrophilic layer solution is a mixture of polyvinylpyrrolidone and deionized water in a volume ratio of 9:1 and ethanol, with a mass percentage concentration of 3%.

[0055] S5: Place the third catheter in an oven at 80°C and cure for 20 minutes. Then raise the temperature to 100°C and continue curing for 2 hours to obtain a water-lubricated, analgesic rubber catheter.

[0056] Comparative Example 1 The main difference between this comparative example and Example 1 is that in step S2, polyacrylic acid and tetracaine hydrochloride in a mass ratio of 1:4 are mixed in an ethanol solution to obtain solution A. The remaining steps and technical parameters are the same as in Example 1.

[0057] The thickness of the adhesion layer is approximately 7 μm, the thickness of the pH-temperature responsive analgesic layer is approximately 50 μm, and the thickness of the hydrophilic layer is approximately 2 μm.

[0058] Comparative Example 2 The main difference between this comparative example and Example 1 is that in step S2, polyacrylic acid and tetracaine hydrochloride in a mass ratio of 1:12 are mixed in an ethanol solution to obtain solution A. The remaining steps and technical parameters are the same as in Example 1.

[0059] The thickness of the adhesion layer is approximately 8 μm, the thickness of the pH-temperature responsive analgesic layer is approximately 55 μm, and the thickness of the hydrophilic layer is approximately 3 μm.

[0060] Comparative Example 3 The main difference between this comparative example and Example 1 is that in step S2, poly(N-isopropylacrylamide) and tetracaproic acid hydrochloride in a mass ratio of 1:3 are mixed in an ethanol solution to obtain solution B. The remaining steps and technical parameters are the same as in Example 1.

[0061] The thickness of the adhesion layer is approximately 7 μm, the thickness of the pH-temperature responsive analgesic layer is approximately 60 μm, and the thickness of the hydrophilic layer is approximately 3 μm.

[0062] Comparative Example 4 The main difference between this comparative example and Example 1 is that in step S2, poly(N-isopropylacrylamide) and tetracaproic acid hydrochloride in a mass ratio of 1:8 are mixed in an ethanol solution to obtain solution B. The remaining steps and technical parameters are the same as in Example 1.

[0063] The adhesion layer has a thickness of approximately 8 μm, the pH-temperature responsive analgesic layer has a thickness of approximately 55 μm, and the hydrophilic layer has a thickness of approximately 3 μm.

[0064] Comparative Example 5 The main difference between this comparative example and Example 1 is that the analgesic layer is coated by an impregnation method. Specifically, the first catheter is placed in a mixed solution of solution A and solution B for 30 seconds, and then dried in an oven at 80°C for 1 hour to obtain the second catheter. The remaining steps and technical parameters are the same as in Example 1.

[0065] The thickness of the adhesion layer is approximately 7 μm, the thickness of the analgesic layer is approximately 9 μm, and the thickness of the hydrophilic layer is approximately 2 μm.

[0066] Comparative Example 6 The main difference between this comparative example and Example 1 is that in step S4, the second catheter is immersed in the hydrophilic layer solution for 30 seconds and then dried in an oven at 80°C for 1 hour to obtain the third catheter. The remaining steps and technical parameters are the same as in Example 1.

[0067] The adhesion layer has a thickness of approximately 7 μm, the pH-temperature responsive analgesic layer has a thickness of approximately 50 μm, and the hydrophilic layer has a thickness of approximately 8 μm.

[0068] Performance testing

[0069] Drug in vitro release experiment: Different release media were set up: Group A, pH 7.4, 37℃ (simulating the urethral environment of a patient under normal conditions); Group B, pH 7.4, 39℃ (simulating the urethral environment of a patient with fever); Group C, pH 8.0, 37℃ (simulating the urethral environment of a patient with infection); Group D, pH 8.0, 39℃ (simulating the urethral environment of a patient with infection and fever). The catheter segments prepared in Example 1 and the comparative example were immersed in the release media of groups A, B, C and D, respectively. Samples were taken at predetermined time points (2h, 6h, 12h, 24h, 2 days, 5 days, 7 days, 10 days and 14 days). Three parallel samples were taken from each group. The drug concentration in the media was tested (HPLC test, model Agilent 1260). The final result was the average value.

[0070] Coefficient of friction: The catheters prepared in the blank group (catheter without coating), the examples and the comparative examples were immersed in the release media of groups A, B, C and D for 14 days, respectively. After being taken out and circulated for 10 times, the coefficient of friction was tested using an MXD-02A coefficient of friction meter. Contact angle: The catheters prepared in the blank group (catheters without coating), the examples and the comparative examples were immersed in the release media of groups A, B, C and D for 14 days and then removed. The contact angle was measured using the droplet method and an Alpha-S contact angle meter.

[0071] Cytotoxicity test (MTT method): The catheters prepared in the blank group (catheter without coating), the examples and the comparative examples were tested for cytotoxicity according to ISO 10993-5 standard. A cytotoxicity rating of 0 or 1 proves that the material is safe.

[0072] Results data

[0073] Table 1. Comparison of drug release test results (μg / mL)

[0074] According to Table 1, the hydrophilic lubricating and analgesic rubber catheter prepared in Example 1 of the present invention, under simulated normal physiological conditions (Group A, pH 7.4, 37℃), showed a slow drug release, with cumulative release amounts of 0.10 μg / mL at 2 h and 3.52 μg / mL at 14 days, demonstrating basic long-acting sustained-release capability. When environmental parameters change towards a pathological state, the release behavior changes significantly: in simulated simple fever (Group B, pH 7.4, 39℃), the thermosensitive side is activated, and the release amount rapidly increases to 0.44 μg / mL in 2 hours (4.4 times that of Group A), and reaches 4.89 μg / mL in 14 days. In simulated simple infection (Group C, pH 8.0, 37℃), the pH response side became dominant, and the release was further accelerated. The release amount at 2h and 14 days reached 0.83μg / mL and 6.93μg / mL, respectively, which was about 1.97 times that under normal conditions, showing a stronger pH-triggered response. Under the dual pathological state of simulated infection combined with fever (Group D, pH 8.0, 39℃), the pH response and temperature response showed a synergistic effect, with the highest release rate and total amount. The release amount reached 0.89 μg / mL in 2 hours and a cumulative release amount of 7.79 μg / mL in 14 days, which is 2.21 times that under normal conditions. Moreover, its total release amount exceeded the arithmetic mean under a single stimulus, which confirmed that the Janus fiber structure achieved a synergistic release effect of "1+1>2". As shown in Table 1, compared with Example 1, in Comparative Example 1, polyacrylic acid and tetracaine hydrochloride were mixed in an ethanol solution at a mass ratio of 1:4 to obtain solution A. In Comparative Example 1, there was too much polymer on the pH-responsive side, and the drug was encapsulated in an excessively thick polymer matrix. Even if swelling occurred, the release rate was too slow. Therefore, even under the conditions of Group D, the released drug concentration was only 5.34 μg / mL on day 14. The drug concentration was too low to achieve the analgesic effect in time.

[0075] According to Table 1, compared with Example 1, in Comparative Example 2, polyacrylic acid and tetracaine hydrochloride in a mass ratio of 1:12 were mixed in an ethanol solution to obtain solution A. In Comparative Example 1, there was too little polymer on the pH-responsive side, which would cause the polymer to fail to form a continuous network, resulting in insufficient mechanical force generated by swelling and a slow drug release rate. Furthermore, drug burst release occurred in groups C and D, resulting in a low concentration of subsequently released drug, which could not meet the requirements for long-term effective analgesia.

[0076] According to Table 1, compared with Example 1, Comparative Example 3 mixed poly(N-isopropylacrylamide) and tetracaproic acid hydrochloride in an ethanol solution at a mass ratio of 1:3 to obtain solution B. The temperature-responsive polymer in Comparative Example 3 was too large, and the overly dense polymer network would hinder drug diffusion, resulting in limited release even under heating conditions.

[0077] As shown in Table 1, compared with Example 1, Comparative Example 4 mixed poly(N-isopropylacrylamide) and tetracaproic acid hydrochloride in an ethanol solution at a mass ratio of 1:8 to obtain solution B. In Comparative Example 3, the amount of polymer on the temperature-responsive side was too small, which resulted in an insignificant phase transition of the temperature-sensitive polymer, making it impossible to effectively regulate drug diffusion and lose its temperature-responsive function. Furthermore, in Comparative Example 4, the drug loading on the pH-responsive side was the same as that on the temperature-responsive side, which could not effectively exert a synergistic effect. Under the dual pathological state of infection combined with fever (Group D), the release rate was slower, and it was impossible to release more drug loading in 14 days.

[0078] As shown in Table 1, compared with Example 1, Comparative Example 5 uses an impregnation method to coat the analgesic layer. After the poly(N-isopropylacrylamide) and polyacrylic acid are mixed, the pH and temperature response signal functions are lost, and the drug release rate is slow.

[0079] As shown in Table 1, compared with Example 1, Comparative Example 6 uses an impregnation method to coat the hydrophilic layer, resulting in a larger hydrophilic layer thickness. The phase change of poly(N-isopropylacrylamide) cannot effectively open the drug diffusion channel, and the drug release rate is slow.

[0080] In summary, the hydrophilic lubricating and analgesic rubber catheter prepared in Example 1 of this invention can accurately sense pathological changes in the urethral microenvironment (pH increase and body temperature rise), and actively and intelligently adjust the release intensity of analgesic drugs to achieve enhanced treatment when needed, thereby potentially significantly improving patient comfort.

[0081] Table 2. Performance comparison of urinary catheters prepared in the examples and comparative examples after immersion in various media for 14 days.

[0082] As shown in Table 2, the hydrophilic lubricating and analgesic rubber urinary catheter prepared by this invention exhibits excellent surface properties. Compared with the uncoated original urinary catheter, the product of this invention can significantly reduce the surface friction coefficient and contact angle. Specifically, the uncoated urinary catheter has a friction coefficient greater than 1.01 and a water contact angle greater than 90° (exhibiting hydrophobicity); while the urinary catheter of this invention can reduce the friction coefficient to below 0.08 and the water contact angle to below 45°, achieving excellent lubrication.

[0083] As shown in Table 2, compared with Example 1, the catheter prepared by Comparative Example 6 using the conventional impregnation method to coat the hydrophilic layer has a dynamic friction coefficient of approximately 0.35 and a water contact angle of approximately 55°. Although this is an improvement over the uncoated sample, its friction coefficient is still more than 7 times that of the product of this invention, and the contact angle is also significantly increased.

[0084] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A hydrophilic, lubricating, analgesic rubber catheter, characterized in that, The surface of the urinary catheter is sequentially coated with an adhesion layer, a pH-temperature responsive analgesic layer, and a hydrophilic layer. The pH-temperature responsive analgesic layer is a Janus fiber felt, with a pH-sensitive polymer and analgesic drug on one side and a temperature-sensitive polymer and analgesic drug on the other side.

2. The hydrophilic lubricating and analgesic rubber catheter according to claim 1, characterized in that, The adhesion layer contains polyurethane, specifically water-based polyurethane. And / or, the hydrophilic layer contains a hydrophilic compound, including one or more of polyvinylpyrrolidone, polyethylene glycol, and hyaluronic acid; And / or, the pH-sensitive polymer includes one or more of polyacrylic acid, acrylic acid copolymers, crosslinked polyacrylic acid, and poly(N,N-dimethylaminoethyl methacrylate); And / or, the temperature-sensitive polymer includes one or more of poly(N-isopropylacrylamide), polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, and polyvinyl methyl ether; And / or, the analgesic includes one or more of tetracaine hydrochloride, lidocaine hydrochloride, and oxybuprocaine hydrochloride.

3. The hydrophilic lubricating and analgesic rubber catheter according to claim 1, characterized in that, The thickness of the adhesion layer is 3-10 μm, the thickness of the pH-temperature responsive analgesic layer is 30-80 μm, and the thickness of the hydrophilic layer is 1-5 μm.

4. A method for preparing a hydrophilic, lubricated, analgesic rubber urinary catheter as described in any one of claims 1-3, characterized in that, Includes the following steps: S1: Perform surface pretreatment on the rubber catheter, and then coat the surface of the pretreated rubber catheter with an adhesion layer to obtain the first catheter; S2: Mix the pH-sensitive polymer and the analgesic drug in a solvent to obtain solution A; mix the temperature-sensitive polymer and the analgesic drug in a solvent to obtain solution B; S3: Inject liquid A and liquid B into the electrospinning equipment for spinning to obtain Janus fiber felt. Then, heat-press the Janus fiber felt onto the surface of the first catheter to obtain the second catheter. S4: Fix the second catheter onto the spin coating device, and drop a hydrophilic layer solution onto its surface until a hydrophilic film is formed to obtain the third catheter; S5: The third catheter is cured by gradient heating to obtain a hydrophilic, lubricated, and analgesic rubber catheter.

5. The method for preparing the hydrophilic, lubricated, and analgesic rubber urinary catheter according to claim 4, characterized in that, In step S1, the surface pretreatment includes the following steps: Low-temperature oxygen plasma treatment of rubber catheters is performed at a power of 60-90W for 40-70s to improve the surface activity and coating adhesion of the rubber catheters. And / or, applying the adhesion layer includes the following steps: Polyurethane is dissolved in deionized water or ethanol solution to prepare a coating solution. The pretreated rubber catheter is immersed in the coating solution and dried to obtain the first catheter. The mass percentage concentration of the coating solution is 5-10%. The soaking time is 30-60 seconds, the drying temperature is 60-80℃, and the drying time is 1-2 hours.

6. The method for preparing the hydrophilic, lubricated, and analgesic rubber urinary catheter according to claim 4, characterized in that, In step S2, the solvent includes deionized water or an ethanol solution; And / or, the mass ratio of pH-sensitive polymer to analgesic drug is 1:5 to 1:10; And / or, the mass percentage concentration of solution A is 8-12%; And / or, the mass ratio of the thermosensitive polymer to the analgesic drug is 1:4 to 1:6; And / or, the mass percentage concentration of solution B is 10-15%; And / or, the total mass of liquid A and liquid B is the same.

7. The method for preparing the hydrophilic, lubricated, and analgesic rubber urinary catheter according to claim 4, characterized in that, The technical parameters of the electrospinning equipment include: The spinning voltage is 15-25 kV, the receiving device is a roller covered with aluminum foil, the distance between the receiving device and the nozzle is 15-25 cm, the temperature is 22-28℃, the humidity is 35-45%, the solution propulsion rate of liquid A and liquid B is 0.8-1.5 mL / h, and the rotation speed of the receiving device is 100-500 rpm. And / or, the hot pressing temperature is 80-100℃, the pressure is 0.1-0.5 MPa, and the hot pressing time is 1-2 min.

8. The method for preparing the hydrophilic, lubricated, and analgesic rubber urinary catheter according to claim 4, characterized in that, In step S4, the hydrophilic layer solution is prepared by placing the hydrophilic compound in a mixed solution of deionized water and ethanol with a volume ratio of 7-9:

1. And / or, the mass percentage concentration of the hydrophilic layer solution is 2-4%.

9. The method for preparing the hydrophilic, lubricated, and analgesic rubber urinary catheter according to claim 4, characterized in that, The spin coating device rotates at 300-500 rpm. The prepared hydrophilic layer solution is added slowly and evenly along the axial direction of the catheter using a pipette to ensure that the solution can instantly wet and cover the entire surface of the fiber felt. Then, the rotation speed is increased to 800-1000 rpm and maintained for 30-60 seconds to allow the solution remaining on the surface of the catheter to spread evenly on the tube wall and quickly level and form a film.

10. The method for preparing the hydrophilic, lubricated, and analgesic rubber urinary catheter according to claim 4, characterized in that, Place the third catheter in an oven at 60-80℃ and cure for 20-30 minutes. Then raise the temperature to 80-100℃ and continue curing for 1-2 hours.

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