CN112121239B

CN112121239B - Airway drug-containing covered stent and preparation method thereof

Info

Publication number: CN112121239B
Application number: CN201910484897.2A
Authority: CN
Inventors: 金方; 闻聪; 雷雨晴; 范新祥; 徐博淳; 郑蒙蒙
Original assignee: Guangzhou Jiankangyuan Respiratory Drug Engineering Technology Co ltd
Current assignee: Guangzhou Jiankangyuan Respiratory Drug Engineering Technology Co ltd
Priority date: 2019-06-05
Filing date: 2019-06-05
Publication date: 2022-10-28
Anticipated expiration: 2039-06-05
Also published as: CN112121239A

Abstract

The invention provides an airway medicated covered stent and a preparation method thereof, wherein the stent comprises a stent body, the stent body is in a net structure and is made of a self-expanding alloy metal material; a blank film is covered on the inner layer of the bracket body, and the blank film is made of a first high polymer material; the outer layer of the bracket body is covered with a drug-containing film, and the drug-containing film is made of a second high polymer material, a drug and a pharmaceutic adjuvant. The drug-containing covered stent can be matched with an airway propeller to be used and sent into a patient body by the airway propeller.

Description

Airway drug-containing covered stent and preparation method thereof

Technical Field

The invention relates to the technical field of medical appliances, in particular to an airway drug-containing covered stent and a preparation method thereof.

Background

The airway stent is an interventional therapy means for various benign or malignant airway stenoses, can relieve the tracheal obstruction symptom of a patient, plays a role in temporary tracheal dilatation or support, and provides opportunities for subsequent further treatment (radiotherapy, chemotherapy and the like). Whether benign or malignant airway stenosis, respiratory endoscopic intervention has become one of the main means for treating airway stenosis, and airway stent implantation is one of the main means for intervention. When surgery or other interventional means fail to achieve a clear airway, placement of an airway stent to maintain a clear breath for the patient may be considered.

In recent years, new stents such as biodegradable stents, drug eluting stents, and radioactive particle stents have been developed. The drug-loaded film-covered metal stent has the advantages that the drugs for resisting cell proliferation, such as paclitaxel, rapamycin, glucocorticoid and the like, are loaded into the film-covered material of the metal stent, so that the trachea can be dilated, the symptoms of dyspnea of a patient and the like can be relieved, and the drug-loaded film-covered metal stent also has the advantages of reducing complications, reducing restenosis after stent implantation and the like. Wherein, the paclitaxel is a drug with good anti-tumor effect, and the paclitaxel eluting blood vessel stent is clinically used for treating coronary artery stenosis as soon as being marketed in 2002, and has the effects of inhibiting the proliferation of vascular smooth muscle and inhibiting restenosis.

At present, no drug eluting airway stent is on the market, the commonly used silicone stent has the defects of difficult implantation and easy displacement in the airway, and the implantation of the self-expanding metal stent is easy to cause the hyperplasia of granulation tissues of the airway so as to cause the restenosis after the implantation of the stent and the difficulty of taking out the stent after the operation. The patent application with publication number CN105232182A and publication number 2016, 1, 13 and named as "an ethylene-vinyl acetate esophageal stent carrying paclitaxel and a preparation method thereof" discloses a coated esophageal stent which can be used for local treatment of the airway of a tumor patient and has the function of supporting and expanding the esophagus by carrying paclitaxel. By referring to the relevant documents of the inventor (Liu, j., et al., biomaterials,2015.53, p.592-599.), the drug eluting stent has the defects that the drug loading amount is large (the maximum drug loading amount is 50%) and the release amount is small (13 days, the release amount is 10.81%;95 days, the release amount is 20.66%), the drug is wasted, the drug concentration at the position where the stent is placed is low, and the drug eluting stent cannot be economically and effectively used.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides an airway drug-containing covered stent, which can improve the drug release rate, so that the drug eluting stent can better achieve the local drug release amount of effective concentration, reduce the drug residue in a drug-loaded membrane after the stent is removed, realize the effective utilization of the drug and reduce the economic burden of a patient.

It is, therefore, an object of the present invention to provide an airway medicated stent graft.

The invention also aims to provide a preparation method of the drug-containing covered stent in the airway.

The above object of the present invention is achieved by the following technical solutions:

on one hand, the invention provides an air flue drug-containing covered stent, which comprises a stent body, wherein the stent body is in a net structure and is made of a self-expanding alloy metal material; a blank film is covered on the inner layer of the bracket body, and the blank film is made of a first high polymer material; the stent is characterized in that a drug-containing film is coated on the outer layer of the stent body and is made of a second high polymer material, a drug and a pharmaceutic adjuvant. The drug-containing covered stent can be matched with an airway propeller to be used and sent into a patient body by the airway propeller.

Preferably, the stent body is cylindrical and has an inner diameter of 5 to 15 mm, preferably 10 mm; a thickness of 0.5 to 0.6 mm, preferably 0.55 mm; the length is 20-80 mm, preferably 50 mm.

Preferably, the stent body is made of a nickel titanium memory alloy material.

Preferably, the first polymer material is a non-degradable polymer material with good thermoplasticity, and is selected from one or more of polylactic acid, polycaprolactone and polylactic acid-glycolic acid copolymer, and is preferably ethylene vinyl acetate copolymer (EVA) or polycaprolactone.

Preferably, the second polymer material is a non-degradable polymer material with better thermoplasticity, is selected from one or more of polylactic acid, polycaprolactone and polylactic acid-glycolic acid copolymer, and is preferably ethylene vinyl acetate copolymer or polycaprolactone.

Preferably, the drug is an anti-tumor drug substance, preferably paclitaxel.

Preferably, the pharmaceutical excipients are selected from dispersants and plasticizers.

Preferably, the dispersant is polyethylene glycol.

Preferably, the plasticizer is HM-530: the polyoxyethylene-polyoxypropylene block copolymer has a number average molecular weight of 6000-8000.

Preferably, the content of the drug in the drug-containing film is 2 to 10wt%, preferably 5wt%.

Preferably, in the drug-containing film, the content of the dispersant is 1 to 4wt%, preferably 2wt%.

Preferably, the content of the plasticizer in the drug-containing film is 1 to 4wt%, preferably 2wt%.

In another aspect, the present invention provides a method for preparing the above airway drug-containing covered stent, comprising:

(1) Covering the outer layer of the stent body with a tetrafluoroethylene film, then immersing the stent body covered with the tetrafluoroethylene film into an organic solution of a first high polymer material, taking out after the stent body is completely immersed, drying in vacuum, and removing the tetrafluoroethylene film on the outer layer to obtain the stent body covered with a blank film;

(2) And (2) rolling and hot-pressing the bracket body coated with the blank film and the hot-pressed medicine-containing film material prepared in the step (1) on a heating platform at 50-80 ℃ and preferably 70 ℃ for 1-10min, preferably 3min, and cooling to bond the bracket body coated with the blank film and the hot-pressed medicine-containing film material.

Preferably, in step (1), the organic solution of the first polymer material is a solution obtained by dissolving the first polymer material in an organic solvent, for example, dichloromethane.

Preferably, the volume ratio between the first polymer material and the organic solvent is 1:4.

Preferably, in the step (2), the preparation method of the hot-pressed drug-containing thin film material comprises the following steps: and melting and blending the second high polymer material, the medicine and the pharmaceutic adjuvant according to a proportion, vacuumizing for 24 hours in a vacuum box, and hot-pressing into a sheet in a hot-pressing forming machine at the temperature of 80 ℃.

The airway drug-containing covered stent can be used for measuring the in vitro drug release by the following method: different airway drug-containing covered stents are placed into phosphate buffer solution (PBS, pH = 7.4) containing 1% Sodium Dodecyl Sulfate (SDS) which meets the condition quantity of a leak groove, the stents are taken out at certain time points (12 h, 1 day, 2 days, 3 days, 5 days, 7 days, 9 days, 12 days, 15 days, 20 days, 25 days, 30 days and 33 days), the same quantity of fresh PBS solution is replaced, the release is continued, finally, the concentration of the taken-out release solution is measured by adopting HPLC, and the taxol content is calculated by using a standard curve method.

Drawings

FIG. 1 is a schematic structural view of an airway medicated stent graft of the present invention;

FIG. 2 is a graph of the drug release ratio of the drug-containing airway stent graft of examples 1-4 of the present invention;

FIG. 3 is a graph showing the daily drug release from the drug-containing stent grafts in the airways of examples 1-4 of the present invention;

FIG. 4 is an SEM photograph of before drug release (0 h) of examples 1-4 of the present invention, wherein the SEM photographs of examples 1, 2, 3 and 4 are shown in sequence in FIG. 4 (a), FIG. 4 (b), FIG. 4 (c) and FIG. 4 (d);

FIG. 5 is an SEM photograph after 33 days of drug release for examples 1-4 of the present invention, wherein FIG. 5 (a), FIG. 5 (b), FIG. 5 (c), and FIG. 5 (d) sequentially show SEM photographs of examples 1, 2, 3, and 4;

FIG. 6 is a graph showing drug release ratios of example 2, comparative example 1, comparative example 3 and comparative example 4 of the present invention; and

FIG. 7 is a graph showing the daily release amount of the drugs of example 2, comparative example 1, comparative example 3 and comparative example 4 of the present invention.

Detailed Description

The invention provides an airway drug-containing covered stent, which is described in detail with reference to the following embodiments and accompanying drawings.

In the following examples, the preparation of the scaffolds is as follows, unless otherwise specified:

FIG. 1 is a drug-containing airway stent of the invention, which comprises a stent body, wherein the stent body is in a reticular structure, the inside and the outside of the stent body are covered with thin films, the inner layer is a blank thin film, and the outer layer is a drug-containing thin film.

The stent body is a cylindrical stent made of a nickel-titanium memory alloy material.

The preparation method of the airway drug-containing covered stent comprises the following steps: sleeving a metal bracket on a proper tetrafluoroethylene rod; wrapping the tetrafluoroethylene film on the bracket and the tetrafluoroethylene rod; taking out the tetrafluoroethylene rod, and only leaving the metal bracket wrapped by the tetrafluoroethylene film; immersing the metal bracket wrapped with the tetrafluoroethylene film and the tetrafluoroethylene film into a first high polymer material solution (the solvent is dichloromethane), taking out after the first high polymer material solution is completely coated, and naturally volatilizing the organic solvent; after the organic solvent is completely volatilized (the operation can be carried out through a vacuum drying oven), the tetrafluoroethylene film is uncovered, and the bracket body covered with the blank film is prepared;

and (2) melting and blending a second high polymer material, paclitaxel (PTX), polyethylene glycol (PEG) and a plasticizer (HM-530) (polyoxyethylene-polyoxypropylene ether block copolymer, the number average molecular weight of which is 6000-8000, cantonese sea lug vegetable oil and fat Co., ltd.) according to a certain proportion, vacuumizing in a vacuum drying oven for 24 hours, and taking out to obtain the uniformly mixed drug-containing film coating material.

Taking out the uniformly mixed drug-containing film-coated material, and hot-pressing the drug-containing film-coated material into slices in a hot-pressing forming machine at the temperature of 80 ℃, wherein the preheating time is 5min, the hot-pressing time is 3min, and the cooling time is 3min;

cutting out a drug-containing tectorial membrane material prepared by hot pressing in advance, wrapping the drug-containing tectorial membrane material on a single-layer tectorial membrane stent, sleeving a tetrafluoroethylene rod on the inner part, wrapping a tetrafluoroethylene membrane on the outer part, heating and pressurizing the stent on a heating flat plate for rolling, cooling and taking out the stent to obtain the airway drug-containing tectorial membrane stent.

In the following examples, the percentages are by mass unless otherwise specified.

Example 1

Firstly, using ethylene vinyl acetate copolymer (EVA) as a first high polymer material to prepare a single-layer blank film-covered stent (i.e. a stent body covered with a blank film), wherein the inner diameter of the single-layer blank film-covered stent is 10 mm, the length of the single-layer blank film-covered stent is 50 mm, and the thickness of the single-layer blank film-covered stent is 0.55 mm; then, using ethylene-vinyl acetate copolymer (EVA) as a second high polymer material, and preparing a drug-containing film coating material according to a certain proportion; and then, rolling and hot-pressing the blank covered stent and the drug-containing covered material on a heating platform at 70 ℃ for 3min, and cooling to combine the blank covered stent and the drug-containing covered material to obtain the airway drug-containing covered stent.

The composition of the drug-containing coating material was 93% by weight of ethylene vinyl acetate copolymer (EVA), 5% by weight of Paclitaxel (PTX), 1% by weight of polyethylene glycol (PEG), and 1% by weight of plasticizer (HM-530).

Example 2

Firstly, using ethylene vinyl acetate copolymer (EVA) as a first high polymer material to prepare a single-layer blank film-covered stent (i.e. a stent body covered with a blank film), wherein the inner diameter of the single-layer blank film-covered stent is 10 mm, the length of the single-layer blank film-covered stent is 50 mm, and the thickness of the single-layer blank film-covered stent is 0.55 mm; then, using ethylene-vinyl acetate copolymer (EVA) as a second high polymer material, and preparing a drug-containing film coating material according to a certain proportion; and then, rolling and hot-pressing the prepared blank covered stent and the drug-containing covered material on a heating platform at 70 ℃ for 3min, and cooling to combine the blank covered stent and the drug-containing covered material to prepare the airway drug-containing covered stent.

The composition of the drug-containing coating material was 91% by weight of ethylene vinyl acetate copolymer (EVA), 5% by weight of Paclitaxel (PTX), 2% by weight of polyethylene glycol (PEG), and 2% by weight of plasticizer (HM-530).

Example 3

The composition of the drug-containing coating material was 89% by weight of ethylene vinyl acetate copolymer (EVA), 5% by weight of Paclitaxel (PTX), 3% by weight of polyethylene glycol (PEG), and 3% by weight of plasticizer (HM-530).

Example 4

Firstly, using ethylene vinyl acetate copolymer (EVA) as a first high polymer material to prepare a single-layer blank film-covered stent (i.e. a stent body covered with a blank film), wherein the inner diameter of the single-layer blank film-covered stent is 10 mm, the length of the stent is 50 mm, and the thickness of the stent is 0.55 mm; then, using ethylene vinyl acetate copolymer (EVA) as a second high polymer material to prepare a drug-containing film coating material according to a certain proportion; and then, rolling and hot-pressing the prepared blank covered stent and the drug-containing covered material on a heating platform at 70 ℃ for 3min, and cooling to combine the blank covered stent and the drug-containing covered material to prepare the drug-containing covered stent for the airway.

The composition of the drug-containing coating material was such that the content of ethylene vinyl acetate copolymer (EVA) was 87% by weight, the content of Paclitaxel (PTX) was 5% by weight, the content of polyethylene glycol (PEG) was 4% by weight, and the content of plasticizer (HM-530) was 4% by weight.

Example 5

Firstly, preparing a single-layer blank film-covered stent (i.e. a stent body covered with a blank film) by using polycaprolactone as a first high polymer material, wherein the inner diameter of the single-layer blank film-covered stent is 13 mm, the length of the stent is 60 mm, and the thickness of the stent is 0.6 mm; then, using polycaprolactone as a second high polymer material to prepare a drug-containing film coating material according to a certain proportion; and then, rolling and hot-pressing the prepared blank covered stent and the drug-containing covered material on a heating platform at 80 ℃ for 2min, and cooling to combine the blank covered stent and the drug-containing covered material to prepare the airway drug-containing covered stent.

The composition of the drug-containing coating material was 88% by weight of ethylene vinyl acetate copolymer (EVA), 10% by weight of Paclitaxel (PTX), 1% by weight of polyethylene glycol (PEG), and 1% by weight of plasticizer (HM-530).

Example 6

The composition of the drug-containing coating material was an ethylene vinyl acetate copolymer (EVA) content of 82% by weight, a Paclitaxel (PTX) content of 10% by weight, a polyethylene glycol (PEG) content of 4% by weight, a plasticizer (HM-530) content of 4% by weight.

Example 7

Firstly, using ethylene vinyl acetate copolymer (EVA) as a first high polymer material to prepare a single-layer blank film-covered stent (i.e. a stent body covered with a blank film), wherein the inner diameter of the single-layer blank film-covered stent is 5 mm, the length of the single-layer blank film-covered stent is 60 mm, and the thickness of the single-layer blank film-covered stent is 0.55 mm; then, using ethylene-vinyl acetate copolymer (EVA) as a second high polymer material, and preparing a drug-containing film coating material according to a certain proportion; and then, rolling and hot-pressing the prepared blank covered stent and the drug-containing covered material on a heating platform at 60 ℃ for 5min, and cooling to combine the blank covered stent and the drug-containing covered material to prepare the airway drug-containing covered stent.

The composition of the drug-containing coating material was such that ethylene vinyl acetate copolymer (EVA) was contained by 90% by weight, paclitaxel (PTX) was contained by 5% by weight, polyethylene glycol (PEG) was contained by 4% by weight, and plasticizer (HM-530) was contained by 1% by weight.

Example 8

Firstly, using ethylene vinyl acetate copolymer (EVA) as a first high polymer material to prepare a single-layer blank film-covered stent (i.e. a stent body covered with a blank film), wherein the inner diameter of the single-layer blank film-covered stent is 15 mm, the length of the single-layer blank film-covered stent is 80 mm, and the thickness of the single-layer blank film-covered stent is 0.55 mm; then, using ethylene-vinyl acetate copolymer (EVA) as a second high polymer material, and preparing a drug-containing film coating material according to a certain proportion; and then, rolling and hot-pressing the prepared blank covered stent and the drug-containing covered material on a heating platform at 70 ℃ for 3min, and cooling to combine the blank covered stent and the drug-containing covered material to prepare the drug-containing covered stent for the airway.

The composition of the drug-containing coating material was such that the content of ethylene vinyl acetate copolymer (EVA) was 90% by weight, the content of Paclitaxel (PTX) was 5% by weight, the content of polyethylene glycol (PEG) was 1% by weight, and the content of plasticizer (HM-530) was 4% by weight.

Comparative example 1

Firstly, using ethylene vinyl acetate copolymer (EVA) as a first high polymer material to prepare a single-layer blank film-covered stent (namely a stent body covered with a blank film), wherein the inner diameter of the single-layer blank film-covered stent is 20 mm, the length of the single-layer blank film-covered stent is 100 mm, and the thickness of the single-layer blank film-covered stent is 0.75 mm; then, using ethylene-vinyl acetate copolymer (EVA) as a second high polymer material, and preparing a drug-containing film coating material according to a certain proportion; and then, rolling and hot-pressing the prepared blank covered stent and the drug-containing covered material on a heating platform at 45 ℃ for 15min, and cooling to combine the blank covered stent and the drug-containing covered material to prepare the airway drug-containing covered stent.

In the drug-containing airway stent of the present invention, the content of ethylene vinyl acetate copolymer (EVA) was 93% by weight, the content of Paclitaxel (PTX) was 5% by weight, the content of polyethylene glycol (PEG) was 2% by weight, and the content of plasticizer (HM-530) was 0% by weight.

Comparative example 2

Firstly, using ethylene vinyl acetate copolymer (EVA) as a first high polymer material to prepare a single-layer blank film-covered stent (namely a stent body covered with a blank film), wherein the inner diameter of the single-layer blank film-covered stent is 20 mm, the length of the single-layer blank film-covered stent is 100 mm, and the thickness of the single-layer blank film-covered stent is 0.75 mm; then, using ethylene vinyl acetate copolymer (EVA) as a second high polymer material to prepare a drug-containing film coating material according to a certain proportion; and then, rolling and hot-pressing the prepared blank covered stent and the drug-containing covered material on a heating platform at 45 ℃ for 15min, and cooling to combine the blank covered stent and the drug-containing covered material to prepare the airway drug-containing covered stent.

In the drug-containing airway stent of the present invention, the content of ethylene vinyl acetate copolymer (EVA) was 93% by weight, the content of Paclitaxel (PTX) was 5% by weight, the content of polyethylene glycol (PEG) was 0% by weight, and the content of plasticizer (HM-530) was 2% by weight.

Comparative example 3

Firstly, using ethylene vinyl acetate copolymer (EVA) as a first high polymer material to prepare a single-layer blank film-covered stent (i.e. a stent body covered with a blank film), wherein the inner diameter of the single-layer blank film-covered stent is 10 mm, the length of the single-layer blank film-covered stent is 5 mm, and the thickness of the single-layer blank film-covered stent is 0.55 mm; then, using ethylene-vinyl acetate copolymer (EVA) as a second high polymer material, and preparing a drug-containing film coating material according to a certain proportion; and then, rolling and hot-pressing the prepared blank covered stent and the drug-containing covered material on a heating platform at the temperature of 80 ℃ for 1min, and cooling to combine the blank covered stent and the drug-containing covered material to prepare the airway drug-containing covered stent.

In the drug-containing airway stent of the present invention, the content of ethylene vinyl acetate copolymer (EVA) was 87% by weight, the content of Paclitaxel (PTX) was 5% by weight, the content of polyethylene glycol (PEG) was 2% by weight, and the content of plasticizer (HM-530) was 6% by weight.

Comparative example 4

Firstly, using ethylene vinyl acetate copolymer (EVA) as a first high polymer material to prepare a single-layer blank film-covered stent (namely a stent body covered with a blank film), wherein the inner diameter of the single-layer blank film-covered stent is 10 mm, the length of the single-layer blank film-covered stent is 50 mm, and the thickness of the single-layer blank film-covered stent is 0.55 mm; then, using ethylene vinyl acetate copolymer (EVA) as a second high polymer material to prepare a drug-containing film coating material according to a certain proportion; and then, rolling and hot-pressing the prepared blank covered stent and the drug-containing covered material on a heating platform at 60 ℃ for 4min, and cooling to combine the blank covered stent and the drug-containing covered material to prepare the drug-containing covered stent for the airway.

In the airway-drug-containing stent graft of the present invention, the content of ethylene vinyl acetate copolymer (EVA) was 85% by weight, the content of Paclitaxel (PTX) was 5% by weight, the content of polyethylene glycol (PEG) was 8% by weight, and the content of plasticizer (HM-530) was 2% by weight.

Comparative example 5

The drug-loaded covered stent is prepared according to the hot pressing preparation method in CN 105232182A. Firstly, preparing a drug-loaded film by using an ethylene-vinyl acetate copolymer (EVA), wherein the drug-loaded film contains 50% of paclitaxel and 50% of EVA, the film is pressed for 4 hours at 120 ℃ by a film pressing machine, the thickness is 0.35 mm, and the length is 25 mm; then, the film was stretched and oriented at 80 ℃ at a speed of 2.5min/r by a factor of 2.5, about 55 mm in length and 0.18 mm in thickness, cooled to room temperature for 30min, removed from the orienting machine, cut, heated by a blower and pressed by tweezers to adhere the film to the metal holder.

Experimental example 1

The drug-containing airway stent grafts described in examples 1 to 4 were placed in phosphate buffered saline (PBS, pH = 7.4) containing 1% Sodium Dodecyl Sulfate (SDS) in an amount satisfying the leak-off condition, the stent was taken out at a predetermined time point (12 h, 1 day, 2 days, 3 days, 5 days, 7 days, 9 days, 12 days, 15 days, 20 days, 25 days, 30 days, 33 days) and replaced with an equal amount of fresh PBS solution, the release was continued, and finally the taken-out release solution was subjected to concentration measurement by HPLC and the paclitaxel content was calculated by a standard curve method.

The measured release rate profiles of the drugs of examples 1 to 4 are shown in FIG. 2, and the daily release rate profile of the drug is shown in FIG. 3.

As can be seen from the drug release profiles, all drug release profiles exhibit two characteristic phases, a rapid drug release phase in the early phase (days 1-3) and a slow drug release phase in the late phase (after day 4). On day 31, the cumulative release rate of paclitaxel from the membranes of different formulations was 63.80% (52.50% -74.32%), 1% (0.86% -1.12%) daily release rate, and 6.92 μ g/cm release rate ² /d。

The results of the in vitro 33-day drug release of comparative examples 1 to 4 show that the percentage of drug release increases with the increase of the additive content, and that the daily release amount also shows a positive correlation. The total release of examples 1-4 was 54.15%, 62.84%, 69.45% and 76.48%, respectively, and it can be seen that the release rate of the drug was adjusted by changing the ratio of the dispersing agent to the plasticizer, thereby achieving the goal of local effective drug concentration.

The 33-day in vitro drug delivery for examples 1-4 is summarized in the following table:

the shapes of the airway drug-containing covered stents described in examples 1-4 before drug release (0 h) and after 33 days of drug release under the experimental conditions are respectively observed under an electron microscope, the SEM pictures observed in the examples 1-4 before drug release (0 h) are sequentially shown in figure 4 (a), figure 4 (b), figure 4 (c) and figure 4 (d), and the SEM pictures observed in the examples 1-4 after 33 days of drug release are sequentially shown in figure 5 (a), figure 5 (b), figure 5 (c) and figure 5 (d).

As seen from SEM pictures before and after drug release, the surface of the film is smooth before drug release, obvious holes appear on the surface of the drug-loaded film after release for one month, and the EVA drug-loaded film has a unidirectional drug slow release effect and can realize long-term local sustained drug release. Moreover, by adding hydrophilic auxiliary materials PEG-1000 and HM-530 and changing the proportion thereof, the method can be used for adjusting the speed of the drug release rate, so that the drug is gradually released along with the dissolution of the additive, and the satisfactory drug release rate is achieved.

Experimental example 2

The drug-containing airway stent-grafts described in example 2 and comparative examples 1 to 4 were placed in phosphate buffered saline (PBS, pH = 7.4) containing 1% Sodium Dodecyl Sulfate (SDS) in an amount satisfying the leak-off condition, the stent-grafts were taken out at certain time points (12 h, 1 day, 2 days, 3 days, 5 days, 7 days, 9 days, 12 days, 15 days, 20 days, 25 days, 30 days, 33 days) and replaced with an equal amount of fresh PBS solution, the release was continued, and finally the taken-out release solution was subjected to concentration measurement by HPLC and the paclitaxel content was calculated by a standard curve method.

As a result, it was found that the total release amounts in one month of example 2 and comparative examples 1 to 4 were 62.84%, 29.05%, 25.15%, 86.89% and 99.29%, respectively, example 2 exhibited an early burst release and a sustained and stable release in the later period, the daily release amount was substantially constant after 20 days, the release amount in the early period of comparative examples 1 to 2 was low, the release amount in the later period was lower than that in the early period, and a sufficient release of the drug could not be achieved. Comparative examples 3-4 release too quickly in the early stage, and release of all the drug is almost completed, and no drug can be released in the later stage, so that effective treatment can not be achieved. The measured release rate profiles of the drugs of example 2, comparative examples 1, 3 and 4 are shown in FIG. 6, and the daily release rate profile of the drug is shown in FIG. 7.

Material	Example 2	Comparative example 1	Comparative example 2	Comparative example 3	Comparative example 4
						EVA(wt％)	91	93	93	87	85
PTX(wt％)	5	5	5	5	5
						HM-530(wt％)	2	0	2	6	2
PEG(wt％)	2	2	0	2	8

Experimental example 3

The drug-containing airway stent grafts described in examples 5 to 8 were placed in phosphate buffered saline (PBS, pH = 7.4) containing 1% Sodium Dodecyl Sulfate (SDS) in an amount satisfying the leak-off condition, the stent was taken out at a certain time point (3 days, 5 days, 9 days, 15 days, 20 days, 33 days) and replaced with an equal amount of fresh PBS solution, the release was continued, and finally the taken-out release solution was subjected to concentration measurement by HPLC and the paclitaxel content was calculated by a standard curve method.

The 33-day in vitro drug release amounts of examples 1 to 4 of experimental example 2 and the 33-day in vitro drug release amounts of examples 5 to 8 are summarized in the following table:

the results show that the percentage of drug release and the daily release amount of the drug increase with the content of the additive, and therefore, the release rate of the drug is adjusted by changing the proportion of the dispersing agent and the plasticizer, so that the purpose of local effective concentration of the drug is achieved. Meanwhile, as can be seen from the results in the above table, example 2 is an optimal scheme, which not only realizes effective local drug release, but also does not release the drug too quickly, thereby ensuring effective drug delivery in the later period and providing ideal therapeutic effect for patients.

Experimental example 4

The drug-containing airway stent graft described in comparative example 5 was placed in a phosphate buffered saline (PBS, pH = 7.4) containing 1% Sodium Dodecyl Sulfate (SDS) in an amount satisfying the leak-off condition, and the stent was taken out at a certain time point (12 h, 1 day, 2 days, 3 days, 5 days, 7 days, 9 days, 12 days, 15 days, 20 days, 25 days, 30 days, 33 days, 45 days, 60 days, 80 days, 90 days) and replaced with an equal amount of fresh PBS solution, followed by release, and finally the taken-out release solution was subjected to concentration measurement by HPLC, and the paclitaxel content thereof was calculated by a standard curve method.

Example 2 compared to comparative example 5 found that the daily drug release of example 2 was about 0.156. + -. 0.062mg/d and the total drug release in 33 days in vitro was about 62.84%; the daily drug release amount of comparative example 5 was about 0.143. + -. 0.056mg/d, and the total drug release amount in vitro was about 57.23% in 90 days, and the results of example 2 were significantly better than those of comparative example 5.

Claims

1. An airway medicated tectorial membrane stent comprises a stent body, wherein the stent body is of a net structure and is made of a self-expanding alloy metal material; a blank film is covered on the inner layer of the bracket body, and the blank film is made of a first high polymer material; the outer layer of the bracket body is covered with a medicine-containing film, and the medicine-containing film is made of a second high polymer material, a medicine and a pharmaceutic adjuvant;

wherein the first high polymer material is ethylene vinyl acetate copolymer (EVA);

the second high polymer material is ethylene-vinyl acetate copolymer;

the pharmaceutic adjuvant is a dispersant and a plasticizer; the dispersing agent is polyethylene glycol; the plasticizer is HM-530: polyoxyethylene-polyoxypropylene ether block copolymer, number average molecular weight is 6000-8000;

in the medicine-containing film, the content of the medicine is 2-10wt%, the content of the dispersing agent is 1-4wt%, and the content of the plasticizer is 1-4wt%;

the preparation method of the airway drug-containing covered stent comprises the following steps:

(2) And (2) rolling and hot-pressing the bracket body coated with the blank film and the hot-pressed medicine-containing film material prepared in the step (1) on a heating platform at the temperature of 50-80 ℃ for 1-10min, and cooling to bond the bracket body coated with the blank film and the hot-pressed medicine-containing film material.

2. The stent of claim 1, wherein the stent body is cylindrical with an inner diameter of 5-15 millimeters; the thickness is 0.5-0.6 mm; the length is 20-80 mm.

3. The stent of claim 1, wherein the stent body is cylindrical with an inner diameter of 10 millimeters; the thickness is 0.55 mm; the length is 50 mm.

4. The stent of claim 1, wherein the stent body is a nitinol material.

5. The stent of claim 1, wherein the drug is an anti-tumor drug substance.

6. The stent of claim 1, wherein the drug is paclitaxel.

7. The stent according to any one of claims 1 to 6, wherein the content of the drug in the drug-containing film is 5wt%.

8. The stent according to any one of claims 1 to 6, wherein the content of the dispersant in the drug-containing film is 2wt%.

9. The stent according to any one of claims 1 to 6, wherein the plasticizer is contained in the drug-containing film in an amount of 2wt%.

10. An airway medicated tectorial membrane stent comprises a stent body, wherein the stent body is of a net structure and is made of a self-expanding alloy metal material; a blank film is covered on the inner layer of the bracket body, and the blank film is made of a first high polymer material ethylene vinyl acetate copolymer; the stent body outer layer is coated with a drug-containing film consisting of 91% by weight of ethylene vinyl acetate copolymer (EVA), 5% by weight of Paclitaxel (PTX), 2% by weight of polyethylene glycol (PEG), 2% by weight of plasticizer polyoxyethylene-polyoxypropylene ether block copolymer.

11. A method of preparing an airway medicated stent graft as claimed in any one of claims 1 to 10 comprising:

12. The preparation method according to claim 11, wherein in the step (2), the blank film-coated stent body prepared in the step (1) and the hot-pressed drug-containing film material are subjected to rolling hot pressing on a heating platform at 50-80 ℃ for 1-10min, and then cooled, so that the blank film-coated stent body and the hot-pressed drug-containing film material are bonded to obtain the drug-containing film material.

13. The production method according to claim 11, wherein in the step (1), the organic solution of the first polymer material is a solution obtained by dissolving the first polymer material in an organic solvent.

14. The production method according to claim 13, wherein, in step (1), the organic solvent is dichloromethane.

15. The production method according to claim 13, wherein a volume ratio between the first polymer material and the organic solvent is 1:4.

16. The method according to any one of claims 11 to 15, wherein in the step (2), the hot-pressed drug-containing thin film material is prepared by: and melting and blending the second high polymer material, the medicine and the pharmaceutic adjuvant according to a proportion, vacuumizing for 24 hours in a vacuum box, and hot-pressing into a sheet in a hot-pressing forming machine at 80 ℃.