Tracheal cannula end balloon and preparation method thereof and tracheal cannula

Abstract

The application relates to the field of medical devices, in particular to a tracheal cannula end balloon, a preparation method thereof and a tracheal cannula. The tracheal cannula end balloon comprises a balloon body and a double-layer structure arranged on the surface of the balloon body, and the double-layer structure comprises a first nanofiber membrane and a second nanofiber membrane; the first nanofiber membrane comprises a first matrix material and paclitaxel, and the first matrix material comprises polyethylene glycol and polycaprolactone; the second nanofiber membrane comprises a second matrix material and ropivacaine, and the second matrix material comprises polyethylene glycol and polyvinylpyrrolidone. In the application, the double-layer structure design realizes layered release of the drugs, the outer-layer drugs rapidly relieve pain and inflammation, and the inner-layer drugs continuously inhibit cell proliferation, so that the problems caused by the tracheal cannula end balloon are comprehensively solved.

Description

Technical Field

[0001] This invention relates to the field of medical devices, specifically to a endotracheal tube end capsule, its preparation method, and an endotracheal tube. Background Technology

[0002] Endotracheal intubation is a common clinical emergency and anesthesia method used to maintain the patency of the patient's airway. However, the balloon at the end of the endotracheal tube is prone to a series of problems when left in the airway for a long time. Existing balloons at the end of endotracheal tubes are usually made of materials such as silicone. Although they have a certain degree of flexibility and biocompatibility, the following problems still exist during long-term placement: (1) Inflammatory reaction: The balloon is in contact with the airway mucosa for a long time, which can easily cause local inflammatory reaction, leading to symptoms such as cough and wheezing in patients. (2) Pain: The pressure and friction of the balloon on the airway mucosa can cause pain and discomfort to patients, affecting their comfort and prognosis (see Brodsky MB, Akst LM, Jedlanek E, et al. Laryngeal Injury and Upper Airway Symptoms After Endotracheal Intubation During Surgery: A Systematic Review and Meta-analysis. Anesth Analg. 2021;132(4):1023-1032). (3) Cell proliferation: Long-term mechanical stimulation and inflammatory response may lead to abnormal proliferation of airway mucosal cells, resulting in tracheal stenosis and even the risk of cancer.

[0003] To address these issues, some studies have attempted to apply drug coatings or modify the materials on the surface of the balloon. For example, Al-Sayed MF, El-Wakad MT, Hassan MA, et al. Novel ten second antimicrobial coating for endotracheal tubes to prevent ventilator-associated pneumonia. Sci Rep. 2026;16(1):1641 discloses a novel ten-second antimicrobial coating for endotracheal tubes to prevent ventilator-associated pneumonia. Chen X, Ling X, Liu G, Xiao J. Antimicrobial Coating: Tracheal Tube Application. Int J Nanomedicine. 2022;17:1483-1494 discloses the application of antimicrobial coatings on endotracheal tubes. Furthermore, in the prior art, CN218739799U discloses an endotracheal tube with a pressure sensor, whose balloon surface is coated with a drug coating, aiming to reduce friction and pressure between the balloon and the airway mucosa through drug release, thereby alleviating inflammation and pain. However, this solution only involves a single drug coating and does not address the dual-layer structure or the synergistic effect of different drugs. CN212997863U discloses a double-lumen saliva drainage device for endotracheal intubation patients, whose balloon surface is coated with a special coating designed to reduce friction and pressure between the balloon and the airway mucosa. However, this solution does not involve a drug coating and only addresses the problem through material modification. CN114870186B discloses an endotracheal tube with an antibacterial coating, whose surface is coated with a polyguanidine coating, prepared by heat treatment and plasma treatment followed by immersion in a polyguanidine aqueous solution. This coating has good antibacterial properties and can reduce related infection complications during endotracheal intubation, but it does not involve drug sustained-release function. CN206228728U discloses a drug sustained-release endotracheal tube, whose balloon and outer surface of the tube are coated with a sustained-release analgesic coating. This coating can slowly release anesthetic drugs, thereby effectively reducing the patient's pain and discomfort during intubation. However, this solution only involves a single drug coating and does not address the synergistic effect of anti-inflammatory drugs.

[0004] It is evident that the solutions disclosed in the existing technologies either only address a single anti-inflammatory or antibacterial problem, or suffer from issues such as uneven drug release and poor coating stability. The endotracheal tube end balloon disclosed in the existing technologies still has room for further improvement. Summary of the Invention

[0005] The purpose of this invention is to provide a endotracheal tube terminal balloon, its preparation method, and an endotracheal tube, which can solve the problems of inflammation, pain, and airway stenosis caused by long-term retention of the endotracheal tube terminal balloon in the airway. At the same time, the bilayer structure can realize the synergistic, layered, and controlled release of two drug molecules.

[0006] To achieve the above objectives, the present invention has the following specific technical solutions:

[0007] In a first aspect, the present invention provides a endotracheal tube end capsule, the endotracheal tube end capsule comprising a capsule substrate and a double-layer structure disposed on its surface, the double-layer structure comprising a first nanofiber membrane and a second nanofiber membrane, the first nanofiber membrane being disposed between the capsule substrate and the second nanofiber membrane; the first nanofiber membrane comprising a first matrix material and a first active drug, the first active drug comprising paclitaxel, the first matrix material comprising polyethylene glycol and polycaprolactone; the second nanofiber membrane comprising a second matrix material and a second active drug, the second active drug comprising ropivacaine, the second matrix material comprising polyethylene glycol and polyvinylpyrrolidone.

[0008] This invention proposes a double-layer coated structure for the end-capillary balloon of an endotracheal tube. This structure features a double-layer coating on the balloon surface: an outer layer of PEO (polyethylene glycol) / PVP (polyvinylpyrrolidone) and an inner layer of PEO / PCL (polycaprolactone). The active drug in the outer layer is ropivacaine, and the active drug in the inner layer is paclitaxel. In this structure, the first matrix material and the first active drug, as well as the second matrix material and the second active drug, exhibit better compatibility. The matching of these different active drugs and matrix materials is more conducive to stable drug release. Furthermore, the ropivacaine in the outer layer effectively relieves pain caused by pressure and friction on the airway mucosa, while the paclitaxel in the inner layer inhibits abnormal proliferation of airway mucosal cells, reducing the incidence of tracheal stenosis. Through the synergistic effect of the two drugs, a sustained-release effect can reduce the probability of inflammatory responses.

[0009] In some embodiments, the mass ratio of polyethylene glycol to polycaprolactone in the first matrix material is 3 to 5:1. This ratio can improve the hydrophilicity of the matrix material, contributing to the uniform distribution of the drug; it also helps improve the flexibility of the first nanofiber membrane and the stable release of paclitaxel. Exemplarily, the mass ratio of polyethylene glycol to polycaprolactone can be 3:1, 4:1, 5:1, or a range of values ​​with any two of these values ​​as endpoints.

[0010] In some embodiments, the mass ratio of polyethylene glycol to polyvinylpyrrolidone in the second matrix material is 1:(1~3). This ratio helps to balance the viscosity and flexibility of the second nanofiber membrane while also contributing to the stable release of ropivacaine. Exemplarily, the mass ratio of polyethylene glycol to polyvinylpyrrolidone can be 1:1, 1:2, 1:3, or a range of values ​​with any two of the above values ​​as endpoints.

[0011] In some embodiments, the weight-average molecular weight of the polyethylene glycol in the first matrix material is 10,000 Da to 20,000 Da. Exemplarily, the weight-average molecular weight of the polyethylene glycol in the first matrix material can be 10,000 Da, 11,000 Da, 12,000 Da, 13,000 Da, 14,000 Da, 15,000 Da, 16,000 Da, 17,000 Da, 18,000 Da, 19,000 Da, 20,000 Da, or a value within a range of any two of these.

[0012] In some embodiments, the weight-average molecular weight of the polycaprolactone in the first matrix material is 50,000 Da to 60,000 Da. Exemplarily, the weight-average molecular weight of the polycaprolactone can be 50,000 Da, 51,000 Da, 52,000 Da, 53,000 Da, 54,000 Da, 55,000 Da, 56,000 Da, 57,000 Da, 58,000 Da, 59,000 Da, 60,000 Da, or a value within a range of any two of these.

[0013] In some embodiments, the weight-average molecular weight of the polyethylene glycol in the second matrix material is 10,000 Da to 20,000 Da. Exemplarily, the weight-average molecular weight of the polyethylene glycol in the second matrix material can be 10,000 Da, 10,500 Da, 11,000 Da, 11,500 Da, 12,000 Da, 12,500 Da, 13,000 Da, 13,500 Da, 14,000 Da, 14,500 Da, 15,000 Da, 15,500 Da, 16,000 Da, 16,500 Da, 17,000 Da, 17,500 Da, 18,000 Da, 18,500 Da, 19,000 Da, 19,500 Da, 20,000 Da, or a value within a range of any two of these.

[0014] In some embodiments, the weight-average molecular weight of the polyvinylpyrrolidone in the second matrix material is 40,000 Da to 60,000 Da. Exemplarily, the weight-average molecular weight of the polyvinylpyrrolidone can be 40,000 Da, 42,000 Da, 44,000 Da, 46,000 Da, 48,000 Da, 50,000 Da, 52,000 Da, 54,000 Da, 56,000 Da, 58,000 Da, 60,000 Da, or a value within a range of any two of these.

[0015] In this application, controlling the molecular weight of PEO / PVP helps improve the viscosity and flexibility of the second nanofiber membrane containing ropivacaine, providing good drug release performance. Conversely, controlling the molecular weight of PEO / PCL helps improve the flexibility of the first nanofiber membrane containing paclitaxel, ensuring the stability of the inner fiber membrane during long-term use.

[0016] In some embodiments, the loading of the first active drug in the first nanofiber membrane is 0.5 wt% to 1.5 wt%. Exemplarily, the loading of the first active drug can be 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, or a value within a range of any two of these.

[0017] In some embodiments, the loading of the second active drug in the second nanofiber membrane is 25 wt% to 40 wt%. Exemplarily, the loading of the second active drug can be 25 wt%, 27 wt%, 29 wt%, 31 wt%, 33 wt%, 35 wt%, 37 wt%, 39 wt%, 40 wt%, or a value within a range of any two of these.

[0018] Secondly, the present invention provides a method for preparing the above-mentioned endotracheal intubation terminal balloon, the method comprising:

[0019] S1: Polyethylene glycol and polycaprolactone are dissolved in a mixed solvent of N,N-dimethylformamide and acetone to obtain a first matrix solution; paclitaxel is dissolved in dimethyl sulfoxide to obtain a first active drug solution; the first matrix solution and the first active drug solution are mixed to obtain a first nanofiber membrane precursor solution;

[0020] S2: The first nanofiber membrane precursor solution is subjected to a first electrospinning treatment to deposit the obtained first nanofiber membrane on the surface of the capsule matrix.

[0021] S3: Polyethylene glycol and polyvinylpyrrolidone are dissolved in a mixed solvent of chloroform and ethanol to obtain a second matrix solution; ropivacaine is dissolved in glycerol to obtain a second active drug solution; the second matrix solution and the second active drug solution are mixed to obtain a second nanofiber membrane precursor solution;

[0022] S4: Perform a second electrospinning treatment on the second nanofiber membrane precursor solution to deposit the obtained second nanofiber membrane on the surface of the first nanofiber membrane.

[0023] In step S1, paclitaxel is mixed with DMSO to form a homogeneous first active drug solution. DMSO, as a solvent, improves the solubility and permeability of paclitaxel. The concentration of paclitaxel in the first active drug solution is 1 μg / ml to 20 μg / ml; optionally, the concentration is 3 μg / ml to 6 μg / ml, which ensures anti-inflammatory and anti-proliferative effects without causing toxicity.

[0024] In step S3, ropivacaine is mixed with glycerol to form a homogeneous second active drug solution. Glycerol, as a solvent, improves the solubility and stability of ropivacaine, facilitating its rapid release while maintaining the flexibility of the fibrous membrane. The concentration of ropivacaine in the second active drug solution is 1 μg / ml to 20 μg / ml, optionally 5 μg / ml to 10 μg / ml, ensuring analgesic efficacy without causing toxicity.

[0025] In some embodiments, the viscosity of the first nanofiber membrane precursor solution is 800 mPa·s to 1200 mPa·s, which is beneficial for forming a uniform and continuous nanofiber structure. Exemplarily, the viscosity of the first nanofiber membrane precursor solution can be 800 mPa·s, 900 mPa·s, 1000 mPa·s, 1100 mPa·s, 1200 mPa·s, or a value within a range of any two of these.

[0026] In some embodiments, the viscosity of the second nanofiber membrane precursor solution is 600 mPa·s to 900 mPa·s, which can effectively regulate the drug release rate and maintain the integrity of the fiber morphology. Exemplarily, the viscosity of the second nanofiber membrane precursor solution can be a value within a range of 600 mPa·s, 700 mPa·s, 800 mPa·s, 900 mPa·s, or any combination thereof.

[0027] In some embodiments, during the first electrospinning process, the static voltage is 12kV~15kV, the feed rate is 0.5ml / h~1.0ml / h, the receiving distance from the capsule to the needle is 10cm~20cm, and the spinning melting temperature is 70℃~80℃.

[0028] In some embodiments, during the second electrospinning process, the static voltage is 12kV~15kV, the feed rate is 0.5ml / h~1.0ml / h, the receiving distance from the capsule to the needle is 10cm~20cm, and the spinning melting temperature is 45℃~55℃.

[0029] In some embodiments, after the first nanofiber membrane is deposited on the surface of the capsule substrate in step S2, the capsule substrate is placed in a vacuum drying oven and dried at 40°C to 45°C for 6 to 8 hours to fully remove residual solvent and enhance the mechanical strength of the fiber membrane; then it is transferred to a sterile container for later use.

[0030] In some embodiments, after the second nanofiber membrane is electrospinned and deposited on the surface of the first nanofiber membrane in step S4, a bilayer structure with gradient release characteristics is formed as a whole; then the capsule is placed in a vacuum drying environment and dried continuously at 40°C~45°C for 6~8 hours to completely remove residual solvent and stabilize the bilayer fiber membrane structure; then it is sterilized by gamma irradiation to ensure the sterility and safety of the product.

[0031] In some embodiments, after the second nanofiber membrane is electrospinned and deposited on the surface of the first nanofiber membrane in step S4, a bilayer structure with gradient release characteristics is formed as a whole.

[0032] In some implementations, S4 is followed by any of the following processing methods:

[0033] The capsules obtained in S4 were subjected to ultraviolet cross-linking irradiation. This treatment achieves surface sterilization while further solidifying the fiber membrane structure, enhancing the interfacial bonding between membrane layers, and effectively preventing the degradation of active ingredients.

[0034] Alternatively, the capsules obtained in S4 can be placed in a vacuum drying environment and dried continuously at 40℃~50℃ for 5h~10h, followed by gamma ray irradiation treatment. The above drying treatment can remove residual solvent while helping to stabilize the bilayer fiber membrane structure; gamma ray irradiation treatment can ensure the sterility and safety of the product.

[0035] In some embodiments, the ultraviolet crosslinking irradiation treatment uses a wavelength of 250nm~260nm, a power of 10W~20W, and an irradiation time of 20min~40min. These conditions ensure that sterilization is achieved while promoting crosslinking reactions between molecular chains, improving the overall stability and sustained-release performance of the material, making it suitable for controllable analgesia needs in long-term implantation scenarios.

[0036] In this application, a mixture of polyethylene glycol and polycaprolactone can form a stable nanofiber membrane through electrospinning, exhibiting good flexibility and biocompatibility. A mixture of polyethylene glycol and polyvinylpyrrolidone can form a more uniform nanofiber membrane through electrospinning, exhibiting good film-forming properties and biocompatibility. Specifically, under the action of an electric field, the first nanofiber membrane precursor solution is stretched into ultrafine fibers and deposited on the surface of the capsule to form an inner layer coating (first nanofiber membrane). The fibrous structure of the inner layer coating provides excellent drug carrier function, enabling slow drug release. The second nanofiber membrane precursor solution is stretched into ultrafine fibers and deposited on the outer side of the inner layer coating to form an outer layer coating (second nanofiber membrane). The aforementioned electrospinning process helps to achieve uniform drug distribution and sustained-release effects.

[0037] In this application, the first and second nanofiber membranes prepared by the above-mentioned electrospinning process have good mechanical and chemical stability, which helps to maintain the uniformity and persistence of drug release during long-term use.

[0038] In this application, in order to improve the adhesion of the capsule surface, increase the surface energy of the capsule, and introduce active groups (such as carboxyl, hydroxyl and amino groups) to facilitate subsequent chemical bonding, the capsule matrix can be plasma treated before electrospinning.

[0039] Thirdly, the present invention also provides an endotracheal tube, wherein it contains the above-mentioned endotracheal tube terminal balloon or the endotracheal tube terminal balloon prepared by the above-mentioned preparation method.

[0040] In this application, the balloon is installed at the end of the endotracheal tube before endotracheal intubation. During intubation, the balloon comes into contact with the airway mucosa, and the drug is gradually released.

[0041] In this application, the bulb substrate of the endotracheal tube distal balloon is made of polyvinyl chloride (PVC) or silicone rubber. PVC and silicone rubber possess good biocompatibility and flexibility, adapting to the physiological structure of the tracheal wall and minimizing tissue irritation or damage during placement. The balloon is sealed to the distal end of the tube via heat fusion or adhesive bonding, effectively sealing the gap between the trachea and the tube after inflation, preventing ventilation leakage and aspiration. The wall thickness of the balloon substrate is controlled within the range of 0.1 mm to 0.3 mm to ensure uniform expansion and rupture resistance.

[0042] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0043] The endotracheal tube terminal balloon and its preparation method provided by this invention, along with the endotracheal tube, feature a double-layer structure design that enables layered drug release. The outer layer drug rapidly relieves pain and inflammation, while the inner layer drug continuously inhibits cell proliferation, thereby comprehensively solving the problems caused by the endotracheal tube terminal balloon.

[0044] In this invention, the descriptions in the specification are merely exemplary and explanatory, and do not limit the scope of protection of this invention. Attached Figure Description

[0045] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0046] Figure 1 This is one of the scanning electron microscope images of the composite fiber membrane of Embodiment 1 provided by the present invention.

[0047] Figure 2 This is the second scanning electron microscope image of the composite fiber membrane of Embodiment 1 provided by the present invention.

[0048] Figure 3 This is the third scanning electron microscope image of the composite fiber membrane of Embodiment 1 provided by the present invention.

[0049] Figure 4 This is the fourth scanning electron microscope image of the composite fiber membrane of Embodiment 1 provided by the present invention.

[0050] Figure 5 This is a scanning electron microscope image of the composite fiber membrane of Example 2 provided by the present invention.

[0051] Figure 6 This is a scanning electron microscope image of the composite fiber membrane of Example 3 provided by the present invention.

[0052] Figure 7 This describes the drug controlled release effect of the capsules in the embodiments and comparative examples provided by the present invention. Detailed Implementation

[0053] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this invention, not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention. In the embodiments provided in this specification, unless specific techniques or conditions are specified, they should be performed according to the techniques or conditions described in the literature in this field, or according to the product instructions. Reagents or instruments used without specified manufacturers are all conventional products that can be purchased through legitimate channels. In the following embodiments, "parts" refers to parts by weight, and the specific unit can be g or kg, etc.

[0054] Terminology Explanation:

[0055] PEO Polyethylene oxide PVP Polyvinylpyrrolidone PCL Polycaprolactone DMSO Dimethyl sulfoxide DMF N,N-dimethylformamide

[0056] In the following embodiments, in the first matrix material, the weight-average molecular weight of polyethylene glycol is 10,000 Da to 20,000 Da, and the weight-average molecular weight of polycaprolactone is 50,000 Da to 60,000 Da. In the second matrix material, the weight-average molecular weight of polyethylene glycol is 10,000 Da to 20,000 Da, and the weight-average molecular weight of polyvinylpyrrolidone is 40,000 Da to 60,000 Da.

[0057] In the following embodiments, the capsule substrate of the endotracheal tube tip is made of polyvinyl chloride or silicone rubber, purchased from Shanghai McLean Biochemical Technology Co., Ltd.

[0058] Example 1

[0059] This embodiment provides a endotracheal tube distal balloon, the preparation method of which includes the following steps:

[0060] S0: Clean and disinfect the capsule substrate to ensure that its surface is clean and free of impurities, and then perform plasma treatment. The plasma treatment parameters are: power 80W, time 120s, and gas is a mixture of oxygen and argon with a volume ratio of 1:3.

[0061] S1: Polyethylene glycol and polycaprolactone in a mass ratio of 3:1 are dissolved in a co-solvent of DMF and acetone to obtain the first matrix solution, wherein the concentration of polyethylene glycol is 0.6 g / ml, the concentration of polycaprolactone is 0.2 g / ml, and the volume ratio of DMF and acetone in the co-solvent is 8:2.

[0062] Paclitaxel was dissolved in dimethyl sulfoxide to obtain a first active drug solution with a paclitaxel concentration of 3 μg / ml;

[0063] The first matrix solution is mixed with the first active drug solution to obtain the first nanofiber membrane precursor solution; the viscosity of the first nanofiber membrane precursor solution is 1000 mPa·s.

[0064] S2: The first nanofiber membrane precursor solution is subjected to a first electrospinning treatment to deposit the resulting first nanofiber membrane onto the surface of the capsule substrate. During the first electrospinning treatment, the electrostatic voltage is 15 kV, the feed rate is 0.8 ml / h, the distance from the capsule to the needle is 15 cm, and the spinning melting temperature is 75 °C, forming a porous fiber membrane layer. The first electrospinning treatment time is 15 min, and the thickness of the resulting first nanofiber membrane is 50 nm. The capsules are dried in a 40 °C oven for 6 hours to completely remove residual solvent from the first nanofiber membrane, ensuring membrane stability and mechanical strength. After drying, the membrane is stored in a sterile environment for later use. The drug loading in the first nanofiber membrane is 0.5 wt%.

[0065] S3: Polyethylene glycol and polyvinylpyrrolidone in a mass ratio of 1:1 are dissolved in a co-solvent of chloroform and ethanol to obtain a second matrix solution, wherein the concentration of polyethylene glycol is 0.2 g / ml, the concentration of polyvinylpyrrolidone is 0.2 g / ml, and the volume ratio of chloroform / ethanol in the co-solvent is 7:3; Ropivacaine is dissolved in glycerol to obtain a second active drug solution with a concentration of 5 μg / ml; The second matrix solution and the second active drug solution are mixed to obtain a second nanofiber membrane precursor solution; The viscosity of the second nanofiber membrane precursor solution is 750 mPa·s.

[0066] S4: The precursor solution of the second nanofiber membrane is subjected to a second electrospinning treatment, and the resulting second nanofiber membrane is deposited on the surface of the first nanofiber membrane to obtain a composite fiber membrane. In the second electrospinning treatment, the electrostatic voltage is 15 kV, the feed rate is 0.8 ml / h, the receiving distance from the capsule to the needle is 15 cm, and the spinning melting temperature is 50 °C, forming a fiber membrane layer with a porous structure; the second electrospinning treatment time is 20 min, and the thickness of the second nanofiber membrane is 100 nm. The drug loading in the second nanofiber membrane is 25 wt%.

[0067] S5: The capsules obtained in S4 are placed in a vacuum drying environment and dried continuously at 40°C for 6 hours to completely remove residual solvent and stabilize the bilayer fiber membrane structure; subsequently, they are sterilized by gamma irradiation to ensure the aseptic safety of the product. After drying, they are stored in a sterile environment for later use.

[0068] Scanning electron microscope images of the composite fiber membrane are shown below. Figures 1-4 .according to Figures 1-4The composite fiber membrane, observed under scanning electron microscopy, exhibits a uniform and continuous fibrous structure with a moderate pore distribution, facilitating sustained drug release. The two membrane layers are tightly bonded, with no obvious delamination, indicating good interfacial compatibility. The final capsule surface coating has a total thickness of approximately 150 nm, possessing excellent mechanical properties and biocompatibility, enabling the phased release of paclitaxel and ropivacaine, and showing potential application value in local tumor treatment and postoperative analgesia.

[0069] Example 2

[0070] The endotracheal tube end capsule provided in this embodiment is similar to that in Embodiment 1, wherein the plasma pretreatment process is the same, the only difference being the preparation process of the double-layer electrospinning deposition fiber membrane:

[0071] S1: Polyethylene glycol and polycaprolactone in a mass ratio of 4:1 are dissolved in a co-solvent of DMF and acetone to obtain the first matrix solution, wherein the concentration of polyethylene glycol is 0.8 g / ml, the concentration of polycaprolactone is 0.2 g / ml, and the volume ratio of DMF and acetone in the co-solvent is 8:2.

[0072] Paclitaxel was dissolved in dimethyl sulfoxide to obtain a first active drug solution with a paclitaxel concentration of 5 μg / ml;

[0073] The first matrix solution is mixed with the first active drug solution to obtain the first nanofiber membrane precursor solution; the viscosity of the first nanofiber membrane precursor solution is 1200 mPa·s.

[0074] S2: The first nanofiber membrane precursor solution is subjected to a first electrospinning treatment to deposit the resulting first nanofiber membrane onto the surface of the capsule substrate. During the first electrospinning treatment, the electrostatic voltage is 12 kV, the feed rate is 1.0 ml / h, the distance from the capsule to the needle is 12 cm, and the spinning melting temperature is 70 °C, forming a porous fiber membrane layer. The first electrospinning treatment time is 30 min, and the thickness of the resulting first nanofiber membrane is 150 nm. The capsules are dried in a 40 °C oven for 6 hours to completely remove residual solvent from the first nanofiber membrane, ensuring membrane stability and mechanical strength. After drying, the membrane is stored in a sterile environment for later use. The drug loading of the first nanofiber membrane is 1.0 wt%.

[0075] S3: Polyethylene glycol and polyvinylpyrrolidone (PVP) in a mass ratio of 1:2 are dissolved in a co-solvent of chloroform and ethanol to obtain a second matrix solution, wherein the concentration of polyethylene glycol is 0.15 g / ml, the concentration of PPV is 0.3 g / ml, and the volume ratio of chloroform to ethanol in the co-solvent is 7:3; Ropivacaine is dissolved in glycerol to obtain a second active drug solution with a concentration of 8 μg / ml; the second matrix solution and the second active drug solution are mixed to obtain a second nanofiber membrane precursor solution; the viscosity of the second nanofiber membrane precursor solution is 1000 mPa·s;

[0076] S4: The precursor solution of the second nanofiber membrane is subjected to a second electrospinning treatment, and the resulting second nanofiber membrane is deposited on the surface of the first nanofiber membrane to obtain a composite fiber membrane. In the second electrospinning treatment, the electrostatic voltage is 12 kV, the feed rate is 1.0 ml / h, the receiving distance from the capsule to the needle is 12 cm, and the spinning melting temperature is 45 °C, forming a fiber membrane layer with a porous structure; the second electrospinning treatment time is 40 min, and the thickness of the second nanofiber membrane is 200 nm. The drug loading in the second nanofiber membrane is 30 wt%.

[0077] S5: The capsules obtained in S4 are placed in a vacuum drying environment and dried continuously at 45°C for 7 hours to completely remove residual solvent and stabilize the double-layer fiber membrane structure; then sterilized by gamma irradiation to ensure the sterility and safety of the product.

[0078] The scanning electron microscope image of the composite fiber membrane in Example 2 is shown below. Figure 5 Scanning electron microscopy revealed a uniform and continuous fibrous structure with a moderate pore distribution, facilitating sustained drug release. The two membrane layers exhibited tight bonding without significant delamination, indicating good interfacial compatibility. The final capsule surface coating had a total thickness of approximately 350 nm, possessing excellent mechanical properties and biocompatibility. It enables the phased release of paclitaxel and ropivacaine, showing potential application value in local tumor treatment and postoperative analgesia.

[0079] Example 3

[0080] The endotracheal tube end capsule provided in this embodiment is similar to that in Embodiment 1, wherein the plasma pretreatment process is the same, the only difference being the preparation process of the double-layer electrospinning deposition fiber membrane:

[0081] S1: Polyethylene glycol and polycaprolactone in a mass ratio of 5:1 are dissolved in a co-solvent of DMF and acetone to obtain a first matrix solution, wherein the concentration of polyethylene glycol is 1.0 g / ml, the concentration of polycaprolactone is 0.2 g / ml, and the volume ratio of DMF to acetone in the co-solvent is 8:2; Paclitaxel is dissolved in dimethyl sulfoxide to obtain a first active drug solution with a paclitaxel concentration of 6 μg / ml; The first matrix solution and the first active drug solution are mixed to obtain a first nanofiber membrane precursor solution; The viscosity of the first nanofiber membrane precursor solution is 800 mPa·s.

[0082] S2: The first nanofiber membrane precursor solution is subjected to a first electrospinning treatment, and the resulting first nanofiber membrane is deposited on the surface of the capsule substrate. During the first electrospinning treatment, the electrostatic voltage is 15 kV, the feed rate is 0.5 ml / h, the distance from the capsule to the needle is 15 cm, and the spinning melting temperature is 80 °C, forming a porous fiber membrane layer. The first electrospinning treatment time is 40 min, and the thickness of the resulting first nanofiber membrane is 200 nm. The capsules are dried in a 40 °C oven for 8 hours to completely remove residual solvent from the first nanofiber membrane, ensuring membrane stability and mechanical strength. After drying, the membrane is stored in a sterile environment for later use. The drug loading of the first nanofiber membrane is 1.5 wt%.

[0083] S3: Polyethylene glycol and polyvinylpyrrolidone in a mass ratio of 1:1 are dissolved in a co-solvent of chloroform and ethanol to obtain a second matrix solution, wherein the concentration of polyethylene glycol is 0.4 g / ml, the concentration of polyvinylpyrrolidone is 0.4 g / ml, and the volume ratio of chloroform / ethanol in the co-solvent is 7:3; Ropivacaine is dissolved in glycerol to obtain a second active drug solution with a concentration of 10 μg / ml; The second matrix solution and the second active drug solution are mixed to obtain a second nanofiber membrane precursor solution; The viscosity of the second nanofiber membrane precursor solution is 600 mPa·s;

[0084] S4: The second nanofiber membrane precursor solution is subjected to a second electrospinning treatment, and the resulting second nanofiber membrane is deposited on the surface of the first nanofiber membrane to obtain a composite fiber membrane. In the second electrospinning treatment, the electrostatic voltage is 15kV, the feed rate is 0.5ml / h, the receiving distance from the capsule to the needle is 15cm, and the spinning melting temperature is 55℃, forming a fiber membrane layer with a porous structure; wherein, the second electrospinning treatment time is 60min, and the thickness of the second nanofiber membrane is 300nm.

[0085] S5: The capsules obtained in S4 were subjected to ultraviolet cross-linking. The ultraviolet light wavelength was set to 254 nm and the power to 15 W, and the irradiation treatment was carried out for 30 minutes to achieve surface sterilization and further solidify the fiber membrane structure, enhance the interfacial bonding force between membrane layers, and effectively prevent the degradation of active ingredients. The drug loading of the second nanofiber membrane was 40 wt%.

[0086] The scanning electron microscope image of the composite fiber membrane in Example 3 is shown below. Figure 6 The composite fiber membrane, observed under scanning electron microscopy, exhibits a uniform and continuous fibrous structure with a moderate pore distribution, facilitating sustained drug release. Ultraviolet cross-linking treatment ensures that sterilization is achieved while promoting inter-chain cross-linking reactions, enhancing the overall stability and sustained-release performance of the material. The final capsule surface coating has a total thickness of approximately 500 nm, possessing excellent mechanical properties and biocompatibility, enabling the phased release of paclitaxel and ropivacaine, suitable for controlled analgesia requirements in long-term implantation scenarios.

[0087] Comparative Example 1

[0088] The only difference between the endotracheal tube end capsule provided in this embodiment and that in Example 1 is that the capsule has a single-layer coating structure, the matrix material is PEO and PVP, and the active drugs are ropivacaine and paclitaxel, with the same dosage as in Example 1.

[0089] Comparative Example 2

[0090] The only difference between the endotracheal tube end capsule provided in this embodiment and that in Example 1 is that the capsule has a single-layer coating structure, the matrix material is PEO and PCL, and the active drugs are ropivacaine and paclitaxel, with the same dosage as in Example 1.

[0091] Test case

[0092] 1. Drug controlled release effect

[0093] Test method: The capsule samples prepared in Examples 1-3 and Comparative Examples 1-2 were placed in phosphate buffer at 37°C. Samples were taken at regular intervals and the contents of ropivacaine and paclitaxel in the release solution were determined by high performance liquid chromatography. The cumulative release curves were plotted.

[0094] Test results: The release rate test results are shown in Table 1 and... Figure 7 .

[0095] Table 1

[0096]

[0097] Comparative Example 1: The hydrophilic PEO / PVP monolayer membrane achieved burst drug release. More than 85% of the drug was released within the first 12 hours, which could not maintain long-term therapeutic effect and had extremely poor uniformity.

[0098] Comparative Example 2: Hydrophobic PEO / PCL monolayer membranes release drugs very slowly. After 168 hours, a large amount of drug may still remain unreleased, resulting in low bioavailability. This makes it difficult to meet the needs of early analgesia. While it has sufficient duration of action, the release rate is uneven.

[0099] Example 1 - Outer layer ropivacaine: Exhibited excellent uniformity and early persistence. Due to the rapid dissolution of PEO / PVP in water, ropivacaine can be released quickly, resulting in rapid analgesia.

[0100] Example 1 - Inner Layer Paclitaxel: Exhibited highly sustained and uniform release. The inner PEO / PCL layer is highly hydrophobic and degrades slowly, providing a long-term stable release pathway for paclitaxel. Its release profile approximates zero-order release kinetics, meaning that an equal amount of drug is released per unit time, which is crucial for long-term inhibition of cell proliferation.

[0101] As can be seen, the total drug release curve of the bilayer structure exhibits a smooth and continuously rising trend, successfully combining an early, appropriate, rapid release with a later, long-term, slow release, achieving synergistic, layered, and controllable release of the two drug molecules. Experiments show that Examples 2-3 have comparable effects to Example 1.

[0102] 2. Coating structure stability

[0103] Test method: The capsule samples prepared in Examples 1-3 and Comparative Examples 1-2 were placed in a medical saline environment at 37°C. They were taken out periodically to observe the changes in the morphology of the coating structure and whether the fibers of the nanofiber membrane layer showed phenomena such as breakage, swelling, or shedding.

[0104] The test results are shown in Table 2:

[0105] Table 2

[0106]

[0107] The experimental results show that the coatings in Examples 1, 2, and 3 remained largely intact within 28 days, with only slight swelling occurring towards the end. No fiber breakage or detachment was observed, indicating that the bilayer structure possesses excellent physical stability and environmental tolerance. Even after rapid erosion of the outer PEO / PVP layer, the overall integrity of the film was maintained, while the inner PEO / PCL layer degraded slowly, effectively supporting long-term structural stability.

[0108] In contrast, Comparative Examples 1-2 typically showed a small number of fiber breaks starting around 7 days, which then intensified the breakage and swelling phenomena, resulting in significant structural damage and further verifying the inadequacy of the monolayer membrane in terms of mechanical properties and dissolution behavior.

[0109] Experimental results show that the bilayer nanofiber membrane structure design of the present invention not only optimizes drug release kinetics, but also significantly improves the service life and clinical reliability of the coating.

[0110] The above are merely embodiments of the present invention and are not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principle of the present invention should be included within the scope of the claims of the present invention.

Claims

1. A balloon at the tip of an endotracheal tube, wherein, The endotracheal tube terminal capsule includes a capsule base and a double-layer structure disposed on its surface. The double-layer structure includes a first nanofiber membrane and a second nanofiber membrane, with the first nanofiber membrane disposed between the capsule base and the second nanofiber membrane. The first nanofiber membrane comprises a first matrix material and a first active drug, wherein the first active drug comprises one or more of paclitaxel, docetaxel and cabazitaxel, and the first matrix material comprises polyethylene glycol and polycaprolactone. The second nanofiber membrane includes a second matrix material and a second active drug, wherein the second active drug includes one or more of ropivacaine, procaine, lidocaine, tetracaine, eticaine, and bupivacaine, and the second matrix material includes polyethylene glycol and polyvinylpyrrolidone.

2. The endotracheal tube distal balloon according to claim 1, wherein, In the first matrix material, the mass ratio of polyethylene glycol to polycaprolactone is (3~5):

1.

3. The endotracheal tube distal balloon according to claim 1 or 2, wherein, In the first matrix material, the weight-average molecular weight of the polyethylene glycol is 10,000 Da to 20,000 Da; and / or, In the first matrix material, the weight-average molecular weight of the polycaprolactone is 50,000 Da to 60,000 Da.

4. The endotracheal tube distal balloon according to any one of claims 1 to 3, wherein, In the second matrix material, the mass ratio of polyethylene glycol to polyvinylpyrrolidone is 1:(1~3).

5. The endotracheal tube distal balloon according to claim 4, wherein, In the second matrix material, the weight-average molecular weight of the polyethylene glycol is 10,000 Da to 20,000 Da; and / or, In the second matrix material, the weight-average molecular weight of the polyvinylpyrrolidone is 40,000 Da to 60,000 Da.

6. The endotracheal tube distal balloon according to any one of claims 1 to 5, wherein, The first nanofiber membrane has an average thickness of 50 nm to 200 nm, and the loading of the first active drug in the first nanofiber membrane is 0.5 wt% to 1.5 wt%; and / or, The average thickness of the second nanofiber membrane is 100 nm to 350 nm, and the loading of the second active drug in the second nanofiber membrane is 25 wt% to 40 wt%.

7. The method for preparing the end-tuberculous balloon according to any one of claims 1 to 6, wherein, The preparation method includes: S1: Polyethylene glycol and polycaprolactone are dissolved in a mixed solvent of N,N-dimethylformamide and acetone to obtain a first matrix solution; paclitaxel is dissolved in dimethyl sulfoxide to obtain a first active drug solution; the first matrix solution and the first active drug solution are mixed to obtain a first nanofiber membrane precursor solution; S2: The first nanofiber membrane precursor solution is subjected to a first electrospinning treatment to deposit the obtained first nanofiber membrane on the surface of the capsule matrix. S3: Polyethylene glycol and polyvinylpyrrolidone are dissolved in a mixed solvent of chloroform and ethanol to obtain a second matrix solution; ropivacaine is dissolved in glycerol to obtain a second active drug solution; the second matrix solution and the second active drug solution are mixed to obtain a second nanofiber membrane precursor solution; S4: Perform a second electrospinning treatment on the second nanofiber membrane precursor solution to deposit the obtained second nanofiber membrane on the surface of the first nanofiber membrane.

8. The method for preparing the endotracheal tube terminal balloon according to claim 7, wherein, The viscosity of the first nanofiber membrane precursor solution is 800 mPa·s to 1200 mPa·s, and / or, The viscosity of the second nanofiber membrane precursor solution is 600 mPa·s to 900 mPa·s.

9. The method for preparing the endotracheal tube distal balloon according to claim 7 or 8, wherein, In the first electrospinning process, the electrostatic voltage is 12kV~15kV, the feed rate is 0.5ml / h~1.0ml / h, the receiving distance from the capsule to the needle is 10cm~20cm, and the spinning melting temperature is 70℃~80℃; and / or, In the second electrospinning process, the static voltage is 12kV~15kV, the feed speed is 0.5ml / h~1.0ml / h, the receiving distance from the capsule to the needle is 10cm~20cm, and the spinning melting temperature is 45℃~55℃.

10. An endotracheal intubation tube, wherein, It contains a endotracheal tube end capsule as described in any one of claims 1 to 6 or an endotracheal tube end capsule prepared by any one of claims 7 to 9.

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