Dual-drug-loading airway stent and preparation method thereof

Abstract

The invention relates to a dual-drug-loading airway stent and a preparation method thereof. A stent body of the dual-drug-loading airway stent is of a tubular structure and comprises an inner layer, an outer layer, a first drug-loading cavity and a second drug-loading cavity, the first drug-loading cavity and the second drug-loading cavity are arranged between the outer layer and the inner layer, a drug-loading film is loaded in the first drug-loading cavity, the drug-loading film comprises a first drug and a light-cured resin material, a hole for releasing the first drug is designed in the corresponding outer layer, and the second drug-loading cavity is provided with a second drug-loading cavity. And a second medicine is accommodated in the second medicine carrying cavity. The dual-drug-loading airway stent not only realizes long-time release of drugs, but also has response release characteristics on chronic inflammatory response microenvironment substances (such as weak acid, hydrogen peroxide and the like), and can perform intelligent response release according to local conditions of a patient. In addition, the dual-drug-loading airway stent can also realize combined use of drugs, and the treatment effect is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical devices, and more particularly to a double drug-loaded airway stent and a preparation method thereof. BACKGROUND

[0002] Airway stenosis is a common respiratory disease caused by tumor, tuberculosis, tracheal intubation, tracheostomy or lung transplantation, etc., which leads to a decrease in the effective ventilation area of the airway. The clinical manifestations are cough, sputum, dyspnea and other symptoms. In severe cases, it can cause suffocation and even endanger life safety. The clinical treatment of airway stenosis includes surgical resection, cryotherapy, thermal ablation or stent implantation, etc., which can quickly relieve the symptoms of dyspnea, has low requirements for heart and lung function, and has the advantages of fast-acting, small damage, etc., and is widely used in clinical applications.

[0003] However, the stent is a foreign body in the airway, which can continuously stimulate the mucosa and cause chronic inflammatory reactions, and is prone to cause excessive proliferation of granulation tissue, thereby leading to the recurrence of airway stenosis (referred to as "restenosis"). Restenosis is closely related to the type of stent material and mechanical pressure. The metal bare stent has a large airway stimulation, and the restenosis rate can reach 5% to 45%. The size and model of the silicone stent are limited, and it cannot be accurately matched with the patient's airway. The size is too large to affect the local microcirculation, and in severe cases, it can cause tissue necrosis. Therefore, according to the different anatomical structures and lesions of the patient's airway, a personalized design is made using 3D technology, a material with excellent biocompatibility is used, and a drug-loaded stent is prepared by loading an anti-scarring drug, which can prevent restenosis by inhibiting the excessive proliferation of granulation tissue, and has good clinical application value.

[0004] A small amount of drug needs to be loaded in the drug-loaded stent to obtain good efficacy, but it poses greater challenges to drug release regulation. The development and treatment of airway stenosis is a long-term process, and it requires stable and controllable drug release for a long time. If the drug is released too quickly, it may have toxic side effects on the normal tissues around the airway, causing complications, which is not conducive to the treatment of airway stenosis. If the drug is released for too short a time, it is difficult to meet the clinical treatment needs (the longest retention time of the stent in the body is 180 days). The metal stent is simple and convenient for drug loading by immersion coating, but the continuous release time is short. The drug-loaded stent with a coating also has the problem of difficult continuous release for a long time. In addition, the same patient has different drug needs in different disease states. For example, in the case of chronic inflammation, the drug needs to have a larger release amount per unit time.

[0005] The Chinese patent entitled "A multi-layer composite structure drug-loaded airway stent and a preparation method thereof" prints an airway stent by hydrophilic modification of TPU to obtain a polyurethane material. On this basis, by adjusting the drug solution formula, the drug can be continuously released for a long period of time, but it cannot adjust the release amount of the drug according to the disease state.

[0006] In addition, the drugs used in the clinic for the treatment of airway stenosis include dexamethasone, paclitaxel, elemene, and mitomycin, and the combination of the drugs can achieve better effects of inhibiting the excessive proliferation of granulation fibroblasts without affecting the normal proliferation of epithelial cells, thereby better preventing airway restenosis. SUMMARY

[0007] The primary object of the present application is to overcome the problem that the existing airway stent does not study the release amount adjustment in response to the airway lesion condition, and to provide a double drug-loaded airway stent. The double drug-loaded airway stent has a stent body in a tubular structure, which includes an inner layer, an outer layer, and a first drug-loaded cavity and a second drug-loaded cavity between the outer layer and the inner layer. The first drug-loaded cavity contains a drug-loaded film, the drug-loaded film includes a drug and a photocurable resin material, and the corresponding outer layer is provided with a hole for releasing the first drug. The second drug-loaded cavity contains a second drug. The double drug-loaded airway stent not only realizes long-term drug release, but also has a response release characteristic to the chronic inflammatory reaction microenvironment substances (such as weak acid, hydrogen peroxide, etc.), and can intelligently respond to the release according to the local condition of the patient. In addition, the double drug-loaded airway stent of the present application can also realize the combination use of drugs, and improve the treatment effect.

[0008] A further object of the present application is to provide a preparation method of the double drug-loaded airway stent.

[0009] The above objects of the present application are achieved by the following technical solutions.

[0010] A double drug-loaded airway stent, which has a stent body in a tubular structure, and the stent body includes an inner layer, an outer layer, and a first drug-loaded cavity and a second drug-loaded cavity between the outer layer and the inner layer.

[0011] The first drug-loaded cavity contains a drug-loaded film, the drug-loaded film includes a first drug and a photocurable resin material; and the outer layer corresponding to the first drug-loaded cavity is provided with a hole for releasing the first drug.

[0012] The photocurable resin material includes the following raw material components by weight:

[0013] 1-5 parts of a surfactant, 20-65 parts of N-vinyl pyrrolidone, 10-45 parts of 2-(dimethylamino)ethyl methacrylate, 10-40 parts of a hydrophobic acrylate monomer, 0.5-5 parts of a multi-functional acrylate monomer, and 0.1-0.5 parts of a photoinitiator;

[0014] The second drug-loaded cavity contains a second drug.

[0015] The material of the stent body is a hydrophilic modified polyurethane.

[0016] In the present application, the outer layer of the first drug-loaded cavity of the drug-loaded membrane of the double-drug-loaded airway stent is provided with holes to provide a channel for the release of the first drug; and the hydrophilic modified polyurethane is used as the material for preparing the stent body, which will gradually dissolve to form micropores in PBS buffer or airway environment, further regulating the release of the first drug.

[0017] The drug-loaded membrane of the double-drug-loaded airway stent of the present application uses a photocured resin material as the carrier material, wherein N-vinyl pyrrolidone is the main component of the photocured resin material, which belongs to a hydrophilic monomer and can undergo a polymerization reaction under the action of a photoinitiator; in order to adjust the hydrophilic and hydrophobic properties of the drug-loaded membrane and regulate the release of the first drug (such as paclitaxel), a certain amount of a hydrophobic acrylate monomer is also added; the addition of a surfactant plays a role as a tackifier, preventing the drug-loaded membrane from flowing out of the holes before curing, and on the other hand, promoting the dissolution of the first drug in the in vivo environment.

[0018] The inventors of the present application found that by adjusting the hydrophilic and hydrophobic properties and solubility of the drug-loaded membrane, adding a certain amount of 2-(dimethylamino)ethyl methacrylate can endow the drug-loaded membrane with an acid-sensitive function, which will accelerate degradation in an acidic environment, thereby enabling the drug-loaded membrane of the double-drug-loaded airway stent to respond to the acidic reaction microenvironment substances in chronic inflammation, to increase the release amount of the first drug. At the same time, through the cooperation of N-vinyl pyrrolidone, 2-(dimethylamino)ethyl methacrylate, hydrophobic acrylate monomer and surfactant, the drug-loaded membrane of the present application can also respond to the free radicals generated by hydrogen peroxide in chronic inflammation, adding the dissolution of the drug-loaded membrane, thereby increasing the release amount of the first drug.

[0019] However, the inventors of the present application found that although the cooperation of the outer layer holes, hydrophilic modified polyurethane and the above-mentioned raw material components of the photocured resin material can achieve the function of adjusting the release amount of the drug according to the disease state of the airway stent, the drug-loaded membrane composed of the above-mentioned components is prone to swelling and breaking in the airway environment, resulting in a shorter sustained release time of the first drug. The inventors of the present application continued to find that adding a certain amount of a multi-functional acrylate monomer, which acts as a crosslinking agent, can make the cured drug-loaded membrane have a three-dimensional crosslinked network of macromolecules without affecting the release function of the drug-loaded membrane in response to chronic inflammation, thereby avoiding the swelling and breaking of the drug-loaded membrane, and enabling the sustained release time of the drug of the drug-loaded membrane to reach a relatively long time.

[0020] That is, through the cooperation of the structural design of the double-drug-loaded airway stent, the material of the stent body and the photocured resin material components of the drug-loaded membrane, the present application not only realizes the long-term release of the drug of the double-drug-loaded airway stent, but also enables the double-drug-loaded airway stent to have the response release characteristics to the microenvironment substances of chronic inflammation reaction (such as weak acid, hydrogen peroxide, etc.).

[0021] In addition, the inner layer of the double drug-loaded airway stent of the present application undertakes the key support function, the hollow design of the inner layer, and the smooth surface of the inner wall is beneficial to the smooth discharge of airway secretions. Moreover, the first drug-loaded cavity is loaded with the first drug, and the second drug-loaded cavity contains the second drug, the first drug and the second drug are both drugs for treating airway stenosis and the first drug and the second drug are different, realizing double drug loading, thereby realizing the combined use of drugs and improving the treatment effect.

[0022] Preferably, the two ends of the outer layer and the inner layer are closed by hot melting.

[0023] Preferably, the thickness of the inner layer can be designed to be 0.3-0.6 mm, the thickness of the outer layer can be designed to be 0.4-0.8 mm, and the thickness of the first drug-loaded cavity and the second drug-loaded cavity can be designed to be 0.4-0.6 mm.

[0024] Preferably, the diameter of the hole is 1.5-2.5 mm.

[0025] Preferably, the number of holes of the outer layer corresponding to the first drug-loaded cavity is 3-8.

[0026] Preferably, the mass ratio of the first drug in the drug-loaded film to the light-cured resin material is (2-4):100.

[0027] Preferably, the light-cured resin material comprises the following raw material components by weight:

[0028] 1.5-3 parts of a surfactant, 25.8-60.3 parts of N-vinyl pyrrolidone, 10-40.7 parts of 2-(dimethylamino)ethyl methacrylate, 10-40 parts of a hydrophobic acrylate monomer, 0.5-3 parts of a multi-functional acrylate monomer, and 0.1-0.5 parts of a photoinitiator.

[0029] Preferably, the surfactant is polyvinyl pyrrolidone.

[0030] More preferably, the polyvinyl pyrrolidone is polyvinyl pyrrolidone K17.

[0031] Preferably, the hydrophobic acrylate monomer is 2-ethylhexyl acrylate.

[0032] Preferably, the multi-functional acrylate monomer is an acrylate monomer containing 3 or more unsaturated C=C bonds.

[0033] More preferably, the multi-functional acrylate monomer is pentaerythritol triacrylate.

[0034] Preferably, the photoinitiator is lithium phenyl(2,4,6-trimethylbenzoyl)phosphinate.

[0035] Preferably, the first and second drugs are both drugs for treating airway stenosis and the first and second drugs are different.

[0036] More preferably, the first drug is paclitaxel.

[0037] More preferably, the second drug is elemene.

[0038] Preferably, the dosage form of the second drug is a solution.

[0039] More preferably, the second drug and the carrier in the solution are used in a ratio of (20-60) mg: 1.5 mL.

[0040] Further preferably, the carrier is a polymer of α-hydro-ω-hydroxyl (oxy-1,2-ethanediyl) with a number average molecular weight of 200-600.

[0041] Preferably, the hydrophilically modified polyurethane comprises the following components in parts by weight: 88-96 parts of polyurethane and 4-12 parts of hydrophilic modifier.

[0042] More preferably, the hydrophilically modified polyurethane comprises the following components in parts by weight: 90-94 parts of polyurethane and 6-10 parts of hydrophilic modifier.

[0043] More preferably, the polyurethane has a melt flow index (MI) of 5-10 g / 10 min (test conditions: 210°C / 2.16 kg) and a hardness of 30-40D.

[0044] More preferably, the polyurethane is a thermoplastic polyurethane.

[0045] More preferably, the hydrophilic modifier is a (propylene oxide-ethylene oxide) copolymer.

[0046] Further preferably, the (propylene oxide-ethylene oxide) copolymer has a number average molecular weight of 8000-13000 and an HLB of 20-30.

[0047] The amount of hydrophilic modifier can be adjusted to achieve a drug release rate under different requirements.

[0048] Preferably, the hydrophilically modified polyurethane is prepared by mixing the polyurethane and the hydrophilic modifier, melting, and extruding and granulating.

[0049] More preferably, the preparation process of the hydrophilic modified polyurethane is: uniformly mixing the polyurethane and the hydrophilic modifier in advance to obtain a premix; melt mixing and granulating the premix by a twin-screw extruder under the conditions of a temperature of 190-220°C and a screw rotation speed of 200-400 rpm to obtain the hydrophilic modified polyurethane; further, using a single-screw extruder to prepare the hydrophilic modified polyurethane into a 3D printing wire with a diameter of 1.75±5 mm.

[0050] The hydrophilic modified polyurethane is used for melt deposition 3D printing to prepare the scaffold body, and further preferably, the filling degree of the 3D printing is 80-100%.

[0051] Preferably, the number of the first drug-loaded cavities is 1-4; and the number of the second drug-loaded cavities is 1-4.

[0052] Preferably, the outer wall of the outer layer is designed with tines.

[0053] The tines have the functions of fixing the scaffold and preventing the scaffold from shifting, and constructing the gap between the scaffold and the airway wall to prevent the retention of secretions.

[0054] More preferably, the tines include a circular truncated cone at the bottom, the bottom surface diameter of the circular truncated cone can be 1.6-2.2 mm, the top surface diameter is 10-20% smaller than the bottom surface diameter, and the height can be 0.8-1.2 mm.

[0055] The top of the circular truncated cone is chamfered to avoid scratching the airway with sharp edges.

[0056] The preparation method of the double-drug-loaded airway scaffold includes the following steps:

[0057] S1. designing the inner layer and the outer layer, and then preparing the scaffold body;

[0058] S2. mixing the raw components of the first drug and the photocurable resin material, then injecting into the first drug-loaded cavity, and curing to load the drug-loaded film in the first drug-loaded cavity; injecting the second drug into the second drug-loaded cavity; obtaining the double-drug-loaded airway scaffold.

[0059] Preferably, the curing process is: uniformly mixing the raw components of the photocurable resin material and the first drug in a light-proof environment to obtain a mixed solution; using a syringe to inject the mixed solution into the first drug-loaded cavity; using a UV curing machine for photocuring, the UV light intensity is 1-3 W / m 2 , the rotation speed of the turntable is 5-30 rpm, the airway scaffold is placed horizontally, the mixed solution is pre-cured for 2-3 min, after the pre-curing of the mixed solution is completed, the airway scaffold is placed vertically and cured for 10-15 min, which completes the loading of the drug-loaded film, and is placed for 24-48 h for standby.

[0060] Compared with the prior art, the present application has the beneficial effects of:

[0061] The dual-drug-loaded airway stent of the present application not only realizes long-term release of drugs, but also has a response release characteristic to chronic inflammatory reaction microenvironment substances (such as weak acid, hydrogen peroxide, etc.), and can intelligently respond and release according to the local condition of the patient. In addition, the dual-drug-loaded airway stent of the present application can also realize the combined use of drugs, thereby improving the treatment effect. BRIEF DESCRIPTION OF DRAWINGS

[0062] Figure 1 is a structural diagram of the dual-drug-loaded airway stent of Examples 1-4; wherein Figure 1 a) is a top view of the dual-drug-loaded airway stent, Figure 1 b) is an axial cross-sectional view of the dual-drug-loaded airway stent; Figure 1 c) is another axial cross-sectional view of the dual-drug-loaded airway stent.

[0063] Figure 2 is a structural diagram of the dual-drug-loaded airway stent of Examples 5-8; wherein Figure 2 a) is a top view of the dual-drug-loaded airway stent, Figure 2 b) is an axial cross-sectional view of the dual-drug-loaded airway stent; Figure 2 c) is another axial cross-sectional view of the dual-drug-loaded airway stent.

[0064] Figure 3 is a three-dimensional view of the dual-drug-loaded airway stent of Examples 1-4.

[0065] Figure 4 is a design drawing of the dual-drug-loaded airway stent of Examples 1-4.

[0066] Figure 5 is a design drawing of the dual-drug-loaded airway stent of Examples 5-8.

[0067] Figure 6 is a structural diagram of the airway stent of Comparative Examples 1-2; wherein Figure 6 a) is a perspective view of the airway stent, Figure 6 b) is a top view of the airway stent; Figure 6 c) is an axial cross-sectional view of the airway stent.

[0068] Figure 7 is a standard curve diagram of paclitaxel and elemene. DETAILED DESCRIPTION

[0069] In order to more clearly and completely describe the technical solutions of the present application, the present application is further described in detail below through specific examples. It should be understood that the specific examples described herein are only used to explain the present application and are not used to limit the present application, and various changes can be made within the scope of the present application.

[0070] It should be noted that when an element is referred to as "provided on" or "provided in" another element, it can be directly on the other element or there can be a middle element. When an element is referred to as "connected to" another element, it can be directly connected to the other element or there can be a middle element. The terms "upper", "lower", "left", "right", and similar expressions used in the present application are only for the purpose of illustration and do not represent the only implementation.

[0071] Examples 1-8

[0072] Examples 1-8 provide a series of double drug-loaded airway stents, wherein, for Examples 1-4, as shown in Figure 1 the double drug-loaded airway stent has a stent body in a tubular structure, and the stent body includes an inner layer 5, an outer layer 3, and an independent cavity 4 between the outer layer and the inner layer, the cavity 4 includes 2 first drug-loading cavities 41 and 2 second drug-loading cavities 42; the outer layer corresponding to each first drug-loading cavity 41 is provided with a hole 1 for releasing a first drug, and the number of holes 1 is 5; the outer wall of the outer layer is designed with a nail tooth 2;

[0073] The first drug-loading cavity 41 is loaded with a drug-loading film, and the second drug-loading cavity 42 is loaded with a solution; the drug-loading film includes paclitaxel and a light-cured resin material; the solution includes elemene and α-hydro-ω-hydroxyl (oxy-1,2-ethanediy) polymer.

[0074] The inner layer 5 is a hollow tubular structure, and the inner wall is a smooth surface, which facilitates the removal of airway secretions and the circulation of gas. The thickness of the inner layer is 0.3-0.6 mm, and in Examples 1-4 it is 0.4 mm. The outer layer 3 is nested outside the inner layer 5, and the thickness of the outer layer is 0.4-0.8 mm, and in Examples 1-4 it is 0.6 mm. The independent cavity between the outer layer and the inner layer is a drug-loading cavity, which is in a hollow structure, and the thickness is 0.4-0.6 mm, and in Examples 1-4 it is 0.5 mm; the diameter of the hole is 1.5-2.5 mm, and in Examples 1-4 it is 2 mm.

[0075] The tines 2 are arranged on the outer wall of the outer layer 3, and specifically, the tines 2 include a bottom circular truncated cone, the bottom surface diameter of the circular truncated cone can be 1.6-2.2 mm, the top surface diameter is 10-20% smaller than the bottom surface diameter, facilitating demolding, and the height can be 0.8-1.2 mm; the top of the circular truncated cone is chamfered to avoid scratching the airway with sharp edges. In Examples 1-4, the bottom surface diameter of the circular truncated cone is 2.2 mm, the top surface diameter is 2.0 mm, and the height is 1.0 mm. The tines 2 have the following effects: fixing the stent, preventing stent displacement; constructing the gap between the stent and the airway wall, preventing retention of secretions.

[0076] Examples 5-8 differ from Example 1 in that, as shown in Figure 2 (outer layer outer wall of the double-drug-loaded airway stent of Examples 5-8 is also designed with tines, which are not shown in Figure 2 ), the cavity 4 includes 3 first drug-loading cavities 41 (corresponding to the outer layer provided with holes for releasing the first drug) and 3 second drug-loading cavities 42; the thicknesses of the inner layer and the outer layer are 0.6 mm and 0.5 mm, respectively; the first drug-loading cavities 41 are loaded with drug-loading films, and the second drug-loading cavities 42 are loaded with solution agents.

[0077] The materials of the stent bodies, the compositions of the drug-loading films, and the solution agents of the examples are shown in Tables 1 and 2.

[0078] The preparation method of the double-drug-loaded airway stents of Examples 1-8 includes the following steps:

[0079] 1) Design the size and shape of the stent body according to the patient's condition (the three-dimensional diagram of Examples 1-4 is shown in Figure 3 );

[0080] 2) Design the inner layer and the outer layer of the stent body, respectively:

[0081] 3) Use 3D printing technology to prepare the stent body (the design of Examples 1-4 is shown in Figure 4 , and the design of Examples 5-8 is shown in Figure 5 );

[0082] 4) In a light-proof environment, mix the raw components of paclitaxel and photocurable resin material uniformly to obtain a mixed solution, use a syringe to inject the mixed solution into the first drug-loading cavity, and place the airway stent horizontally under the condition of a UV light intensity of 1.5 W / m 2 and a turntable speed of 10 rpm; the mixed solution is pre-cured for 2 min, and after the pre-curing of the mixed solution is completed, the airway stent is placed vertically and cured for 13 min to form a drug-loading film, i.e., the loading of paclitaxel is completed, and the airway stent is placed for 24 h for standby; dissolve elemane in a drug carrier, use a syringe to inject the elemane into the second drug-loading cavity, and then heat and melt to seal the needle holes for loading, thereby obtaining a series of double-drug-loaded airway stents.

[0083] The material of the stent body in Examples 1-8 is hydrophilic modified polyurethane, which is prepared by the following method: polyurethane and (propylene oxide-ethylene oxide) copolymer are uniformly mixed in advance to obtain a premix, and the premix is melt-mixed and granulated by using a twin-screw extruder under the conditions of a temperature of 200-220°C and a rotation speed of 200-400 rpm.

[0084] Comparative Examples 1-2

[0085] Comparative Examples 1-2 provide a series of airway stents, which are different from Example 1 in that: 1) the paclitaxel in the first drug-loaded cavity in Comparative Examples 1-2 is loaded in the form of a solution, and the outer layer of the first drug-loaded cavity has no holes, as shown in Figure 6 ; 2) the material of the stent body or the composition of the solution in each comparative example is different, as shown in Table 3.

[0086] The preparation method of the airway stents in Comparative Examples 1-2 is basically the same as that in Example 1.

[0087] Comparative Examples 3-4

[0088] Comparative Examples 3-4 provide a series of airway stents, which are different from Example 1 in that: the material of the stent body, the composition of the drug-loaded film or the solution is different, as shown in Table 3.

[0089] The preparation method of the airway stents in Comparative Examples 3-4 is basically the same as that in Example 1.

[0090] Performance test

[0091] The materials and airway stents of Examples 1-8 and Comparative Examples 1-4 are subjected to the following tests, and the test results are shown in Tables 1, 2 and 3.

[0092] Static contact angle test: polyurethane and hydrophilic modified polyurethane (i.e. the material of the stent body in each example and comparative example) are pressed into a sheet with a thickness of 0.5 mm, and a test sample with a size of 10x10 mm is cut, and a contact angle measuring instrument is used to measure the static contact angle of the material, and deionized water is used as the test liquid, and the drop volume is 2 μL.

[0093] The performance test of the airway stent includes radial compression force, compression strength, drug release behavior (drug sustained release time and drug cumulative release amount).

[0094] The radial compression force and compression strength are tested by using an electronic universal testing machine, and the method is described in GB / T 1041-2008 standard. The diameter is placed in the middle of the compression mold, and the pressure is applied along the diameter direction, and the maximum force, compression strength and compression modulus when the diameter compression strain is 30% are tested.

[0095] Drug release behavior: The HPLC method was used for determination, and the HPLC system was composed of a binary pump, a 1290 injector, a temperature control module and a 1290 DAD detector. The chromatographic column was Agilent ODS C18 column (5 mm x 4.6 mm x 250 mm), the detection wavelength was 210 nm, 227 nm, the data processing software was chemstation for LC 3D system, the mobile phase was 7% phosphoric acid aqueous solution (phosphoric acid mass content 0.1%) and 93% acetonitrile gradient elution (0-8 min, 60% acetonitrile; 12-22 min, 98% acetonitrile; 23-28 min, 60% acetonitrile), the flow rate was 1 mL / min, the injection amount was 10 μL, and the column temperature was 25 °C.

[0096] Preparation of paclitaxel and elemene standard samples: 0.2002 g of paclitaxel reference substance and 0.2112 g of elemene reference substance were precisely weighed into a 100 mL brown volumetric flask, dissolved with chromatographic grade methanol by ultrasonic, and then diluted to volume to obtain a mixed reference substance stock mother liquor 1 (containing 2.002 mg / mL of paclitaxel and 2.112 mg / mL of elemene), which was stored at 4 °C.

[0097] M-1 (200): 1 mL of mother liquor 1 was precisely measured and transferred to a 10 mL volumetric flask, which was diluted to volume with chromatographic grade methanol to obtain M-1 (containing 200.2 μg / mL of paclitaxel and 211.2 μg / mL of elemene).

[0098] M-2 (100): 5 mL of mother liquor 1 was precisely measured and transferred to a 100 mL volumetric flask, which was diluted to volume with chromatographic grade methanol to obtain M-2, i.e. mother liquor 2 (containing 100.1 μg / mL of paclitaxel and 105.6 μg / mL of elemene).

[0099] M-3 (25): 2.5 mL of mother liquor 2 was precisely measured and transferred to a 10 mL volumetric flask, which was diluted to volume with chromatographic grade methanol to obtain M-3 (containing 25.025 μg / mL of paclitaxel and 26.4 μg / mL of elemene).

[0100] M-4 (10): 1 mL of mother liquor 2 was precisely measured and transferred to a 10 mL volumetric flask, which was diluted to volume with chromatographic grade methanol to obtain M-4 (containing 10.01 μg / mL of paclitaxel and 10.56 μg / mL of elemene).

[0101] M-5 (5): 500 μL of mother liquor 2 was precisely measured and transferred to a 10 mL volumetric flask, which was diluted to volume with chromatographic grade methanol to obtain M-5 (containing 5.005 μg / mL of paclitaxel and 5.28 μg / mL of elemene).

[0102] M-6(1): 100 μL of mother liquor 2 was precisely measured and transferred into a 10 mL volumetric flask, which was diluted with chromatographic grade methanol to the mark, and M-6 (containing paclitaxel 1.001 μg / mL, elemene 1.056 μg / mL) was obtained.

[0103] M-7(0.5): 50 μL of mother liquor 2 was precisely measured and transferred into a 10 mL volumetric flask, which was diluted with chromatographic grade methanol to the mark, and M-7 (containing paclitaxel 0.5005 μg / mL, elemene 0.528 μg / mL) was obtained.

[0104] Standard curve fitting: The paclitaxel and elemene drug peak areas in the high performance liquid chromatograph were input into GraphPad 10 corresponding to the known drug standard sample concentration, and a scatter plot was drawn and linear regression fitting was performed, and the results are shown in Figure 7 Figure 7 A is the standard curve of paclitaxel, Figure 7 B is the standard curve of elemene, and the R 2 of the standard curves of the two drugs in the fitting results is greater than 0.99, and R is greater than 0.999, and the fitting effect is good. Therefore, it is determined that the paclitaxel drug standard curve is Y = 20.113X-16.805, and the drug concentration range is (0.5-200 μg / mL); the elemene drug standard curve is Y = 8.8537X-0.3853, and the drug concentration range is (0.5-200 μg / mL).

[0105] In vitro drug release test of drug-loaded stents: The stent was placed in a 50 mL centrifuge tube with a cover, and four different extraction solutions were added according to the sample: extraction solution = 1 g:5 mL ratio: 1% SDS PBS (pH 7.4) solution, H2O2 aqueous solution (7.5 ppm), pH 5.5 weak acid solution (1% sodium dihydrogen phosphate solution), H2O2 + pH 5.5 solution (1% sodium dihydrogen phosphate solution added with 7.5 ppm H2O2) to simulate the in vivo liquid environment. The centrifuge tube was placed in a constant temperature shaking bath, and the temperature was kept at 37°C and the speed was 70 r / min. At a certain time point, the centrifuge tube was taken out, and the stent was taken out, the surface residual solution was absorbed with filter paper, and then placed in fresh 40 mL extraction solution and returned to the shaking bath for continuous release.

[0106] The concentrations of the two drugs in the airway stent release solution were determined by the above HPLC method, and the sample was filtered with a 0.45 μm filter membrane after shaking.

[0107] The daily release amount of the drug was continuously tested, and the number of days continuously maintaining more than 0.2% was calculated, and the cumulative release amount was accumulated to obtain the cumulative release amount. The continuous release days were calculated based on the time point when the drug release amount in the stent was ≤0.2% or the longest 120 days. The cumulative release amount was divided by the continuous release days, and the average release amount was obtained.​

[0108] Table 1 Material formulation, loading formulation and performance test results of examples 1-4

[0109]

[0110]

[0111] Table 2 Material formulation, loading formulation and performance test results of examples 5-8

[0112]

[0113]

[0114] From the test results of examples 1-8 in Table 1, when the paclitaxel of the double-drug-loaded airway stent is loaded by the drug-loaded film, the average daily release amount in the microenvironment of H2O2, pH 5.5 and H2O2+pH 5.5 is higher than that in the PBS solution, indicating that the double-drug-loaded airway stent of the application has the function of responding to weak acid and hydrogen peroxide to accelerate release, and can intelligently respond to release according to the local condition of the patient. In addition, the double-drug-loaded airway stent of the application can realize long-term drug release, and the release time in the environment of H2O2+pH 5.5 reaches 120 days.

[0115] Table 3 Material formulation, loading formulation and performance test results of comparative examples 1-4

[0116]

[0117]

[0118] From the test results of comparative examples 1-2 in Table 3, the α-hydro-ω-hydroxyl (oxy-1,2-ethanediy) polymer is used to load paclitaxel (i.e. the dosage form is a solution), the sustained release time of paclitaxel is short (≤51 days), and the release amount in weak acid and / or peroxide is not improved relative to the PBS solution, i.e. it does not have the release characteristic of responding to the microenvironment substances of chronic inflammatory response.

[0119] The light-cured resin material of the airway stent of comparative example 3 does not add 2-(dimethylamino)ethyl methacrylate, and the release amount in the environment of acid and / or peroxide does not increase, and does not have the release characteristic of responding to the microenvironment substances of chronic inflammatory response; the light-cured resin material of the airway stent of comparative example 4 does not add pentaerythritol triacrylate, and the release time of the drug is shorter than that of example 2.

[0120] The double drug-loaded airway stent prepared by the preparation method can load other drugs, and the drug-loaded film is cured by ultraviolet light to endow the stent with the response characteristic regulation and drug release to weak acid and peroxide, can regulate the release behavior of paclitaxel, and meets the needs of continuous long-time drug administration in clinical treatment. After the double drug-loaded airway stent is implanted, the airway cross section can be immediately expanded to relieve the symptoms of respiratory distress, the chronic inflammatory reaction is reduced by the drug, the fibroblast mitosis is inhibited, the excessive proliferation of granulation tissue is prevented, the repeated restenosis problem in the clinical treatment of airway stenosis is solved, and the double drug-loaded airway stent has a good clinical application prospect.

[0121] Obviously, the above embodiments of the present application are only examples for clearly illustrating the present application, and are not intended to limit the embodiments of the present application. Based on the above description, other different forms of changes or variations can be made by those skilled in the art. Here, all the embodiments are not required to be exhausted. Any modification, equivalent replacement and improvement made within the spirit and principle of the present application shall be included in the protection scope of the claims of the present application.

Claims

1. A dual drug-loaded airway stent, characterized in that, The double-drug-loaded airway stent has a stent body in a tubular structure, and the stent body comprises an inner layer, an outer layer, and a first drug-loaded cavity and a second drug-loaded cavity between the outer layer and the inner layer; The first drug-loaded cavity contains a drug-loaded film, and the drug-loaded film comprises a first drug and a photocured resin material; the corresponding outer layer of the first drug-loaded cavity is provided with a hole for releasing the first drug; The photocured resin material comprises the following raw material components by weight fraction: 1-5 parts of a surfactant, 20-65 parts of N-vinyl pyrrolidone, 10-45 parts of 2-(dimethylamino)ethyl methacrylate, 10-40 parts of a hydrophobic acrylate monomer, 0.5-5 parts of a multi-functional acrylate monomer, and 0.1-0.5 parts of a photoinitiator; The second drug-loaded cavity contains a second drug; The material of the stent body is a hydrophilic modified polyurethane.

2. The dual drug-loaded airway stent of claim 1, wherein, The diameter of the hole is 1.5-2.5 mm.

3. The dual drug-loaded airway stent of claim 1, wherein, The mass ratio of the first drug to the photocured resin material in the drug-loaded film is (2-4):

100.

4. The dual drug-loaded airway stent of claim 1, wherein, The hydrophobic acrylate monomer is 2-ethylhexyl acrylate.

5. The dual drug-loaded airway stent of claim 1, wherein, The dosage form of the second drug is a solution.

6. The dual drug-loaded airway stent of claim 1, wherein, The hydrophilic modified polyurethane comprises the following components by weight fraction: 88-96 parts of polyurethane and 4-12 parts of a hydrophilic modifier.

7. The dual-drug loaded airway stent of claim 6, wherein, The hydrophilic modifier is a (propylene oxide-ethylene oxide) copolymer.

8. The dual drug-loaded airway stent of claim 1, wherein, The number of the first drug-loaded cavities is 1-4; the number of the second drug-loaded cavities is 1-4.

9. The dual drug-loaded airway stent of claim 1, wherein, The outer wall of the outer layer is designed with a tine.

10. The method of making a dual drug-loaded airway stent of any one of claims 1-9, wherein, The method comprises the following steps: S1. Designing the inner layer and the outer layer, and then preparing the stent body; S2. Mixing the raw material components of the first drug and the photocured resin material, then injecting them into the first drug-loaded cavity, and curing to load the drug-loaded film in the first drug-loaded cavity; injecting the second drug into the second drug-loaded cavity; thus obtaining the double-drug-loaded airway stent.

Images