CN113041407A

CN113041407A - Multilayer film-covered drug-loaded stent and preparation method and application thereof

Info

Publication number: CN113041407A
Application number: CN202110275503.XA
Authority: CN
Inventors: 金方; 周劼; 闻聪; 甘瑜
Original assignee: Shanghai Fangyu Health Pharmaceutical Technology Co ltd; Guangzhou Jiankangyuan Respiratory Drug Engineering Technology Co ltd
Current assignee: Shanghai Fangyu Health Pharmaceutical Technology Co ltd; Guangzhou Jiankangyuan Respiratory Drug Engineering Technology Co ltd
Priority date: 2021-03-15
Filing date: 2021-03-15
Publication date: 2021-06-29
Anticipated expiration: 2041-03-15
Also published as: CN113041407B

Abstract

The invention provides a multilayer film-coated drug-loaded stent and a preparation method and application thereof. The drug-loaded stent solves the problem of restenosis caused by the growth of granulation tissues or tumor cells by releasing drugs.

Description

Multilayer film-covered drug-loaded stent and preparation method and application thereof

Technical Field

The invention relates to the technical field of medical instruments, in particular to a multilayer film-coated drug-loaded stent and a preparation method and application thereof.

Background

Tracheal stenosis is a common respiratory disease, and is often caused by endotracheal intubation, infection, trauma, congenital disease, malignant tumor, and the like. With the increasing incidence of tumor and the wide application of the breathing machine assisted breathing technology in the treatment of patients with tracheal trauma, the incidence of tracheal stenosis is obviously increased. Clinically, stent intervention is an effective treatment means. However, naked stent placement tends to irritate airway mucosa, leading to a series of complications such as granulation tissue hyperplasia and chronic inflammation, resulting in-stent restenosis, which greatly limits the clinical use of tracheal stents.

The covered stent is formed by coating a metal stent with a special film material, such as polytetrafluoroethylene, dacron, polyester, polyurethane and the like. The film-covered stent not only retains the function of a metal stent, but also has the characteristics of a film material. Most of the existing covered stents are single-layer blank membrane stents or single-layer drug-loaded stents, wherein the single-layer blank membrane stents only physically prevent tumor tissues and the like from penetrating through the stent and entering into a stent cavity. The drug-loaded stent is also called a Drug Eluting Stent (DES), and a bare metal stent platform is used for carrying drugs and locally eluting and releasing the drugs. The drug-loaded stent can expand the narrow part of the airway by the physical property of the metal stent, and the drug loaded on the surface of the stent can solve the problem of restenosis in the stent by the pharmacological actions of inhibiting granulation tissue proliferation, inhibiting cell proliferation and the like.

However, the existing stent graft has the following problems: 1. after the single-layer medicine-carrying stent is placed in a body, body fluid can elute an exposed stent medicine film, so that some medicines flow into a pipeline and cannot play a role in local treatment; 2. when a stent drug film is prepared by using a dip coating method or a hot pressing film preparation method, the thickness and the uniformity of the drug film are often difficult to control.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a one-way release multilayer tectorial membrane drug-loaded stent and a preparation method thereof. The preparation method provided by the invention is simple in process and convenient to operate, and can effectively control the thickness of the medicine film and the uniformity of the medicine.

In order to achieve the purpose, the invention adopts the following technical scheme:

in one aspect, the invention provides a multilayer film-coated drug-loaded stent, which comprises a stent body, a blank film and a drug-loaded film, wherein the blank film is coated on the surface of the stent body, and the drug-loaded film is coated on the surface of the blank film; wherein the drug-loaded membrane contains a drug active component, a pore-forming agent and a second non-biodegradable high molecular material.

Preferably, the blank film is a first non-biodegradable polymer material;

preferably, the first non-biodegradable polymer material is selected from one or more of polyurethane, silicone rubber and polytetrafluoroethylene, and is preferably silicone rubber.

Preferably, the content of the pharmaceutical active ingredient in the drug-loaded film is 0.12 wt.% to 30.24 wt.%; the content of the pore-forming agent is 0.11-45.98 wt.%; the content of the second non-biodegradable high polymer material is 50.21-99.40 wt.%.

Preferably, the porogen is present in an amount of 0.30-25.12 wt.%, preferably 10.00-25.00 wt.%; preferably, the content of the pharmaceutically active ingredient is 0.21-15.73 wt.%, preferably 0.20-5.00 wt.%.

Preferably, the drug-loaded film does not contain a plasticizer, such as polyoxyethylene-polyoxypropylene ether block copolymer HM-530 with a number average molecular weight of 6000-8000.

Preferably, the drug-loaded membrane consists of a pharmaceutical active ingredient, a pore-forming agent and a second non-biodegradable high molecular material.

Preferably, the active pharmaceutical ingredient is selected from antitumor drugs selected from rapamycin, paclitaxel derivatives, elvucimus, tacrolimus, emodin, heparin, hirudin, and the like, preferably paclitaxel or rapamycin.

Preferably, the porogen is selected from one or more of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) and Hydroxypropylmethylcellulose (HPMC), preferably PVP.

Preferably, the second non-biodegradable polymer material is selected from one or more of polyurethane, silicone rubber and polytetrafluoroethylene, and is preferably silicone rubber.

Preferably, the thickness of the blank film or the drug-loaded film is 10-500 μm; preferably, the thickness of the blank film or the drug-loaded film is 15-150 μm.

Preferably, the stent body is a metal porous mesh structure.

In another aspect, the invention provides a preparation method of the multilayer covered drug-loaded stent, which comprises the following steps:

step a): dissolving a first non-biodegradable high polymer material by using a first organic solvent, soaking and drying a metal bare stent in the first non-biodegradable high polymer material, and forming a blank film on the surface of the stent;

step b): dissolving a second non-biodegradable high polymer material to proper viscosity by using a second organic solvent, mixing a medicinal active ingredient and a pore-forming agent, dissolving by using a third organic solvent, and uniformly mixing the two solutions to obtain a mixed solution containing the medicament, the pore-forming agent and the high polymer material; spraying the mixed solution on the surface of a blank film by ultrasonic spraying equipment or electrostatic spraying equipment, and drying to form a drug-loaded film on the surface of the blank film;

preferably, in step a), the first organic solvent is selected from the group consisting of petroleum ether, acetone, dichloromethane, diethyl ether, ethyl acetate, chloroform, dimethyl sulfoxide and ethanol, preferably petroleum ether or dichloromethane;

preferably, in the step a), the soaking time is 1-5 minutes, and the soaking is repeated for 2-6 times;

preferably, in step b), the second organic solvent is selected from petroleum ether, acetone, dichloromethane, diethyl ether, ethyl acetate, chloroform, dimethyl sulfoxide and ethanol, preferably petroleum ether or dichloromethane;

preferably, in step b), the third organic solvent is selected from dichloromethane, ethanol, methanol, chloroform and dimethyl sulfoxide, preferably ethanol;

preferably, in the step b), the viscosity is 1.00-10.00 cp;

preferably, in the step b), the flow rate of the ultrasonic spraying equipment during spraying is 0.01-1.2 ml/min, and preferably 0.2-0.6 ml/min; the power of the ultrasonic spray head is 0.5-1.5W; the frequency is 40-65 kHz; the spraying times are 2-70 times, preferably 3-10 times; the moving speed is 1-10mm/s, preferably 1-3 mm/s; the rotational speed is 1 to 10r/s, preferably 1 to 3 r/s.

In a further aspect, the invention provides the use of the multilayer covered membrane drug-loaded stent, which is used for lumen stenosis and obstruction caused by pathological changes;

preferably, the lesion is selected from congenital diseases, surgery, burns, radioactive injuries, interventions, infections and malignancies;

preferably, the lumen is selected from the group consisting of esophagus, bile duct, pancreatic duct, intestinal tract, urethra, trachea, bronchi.

Compared with the prior art, the invention has the following advantages:

the application provides a multilayer tectorial membrane medicine carrying air flue support, through the constitution and the content of adjusting the medicine carrying support, support medicine accumulation release degree is high, and 29 days medicine accumulation release can reach 80% at most. Meanwhile, the burst release of the medicine is small in the early stage, and the medicine can be continuously and slowly released in the later stage, so that the aim of long-term treatment is fulfilled.

The ultrasonic spraying process is used for preparing the specific drug-loaded membrane, the membrane thickness can be effectively controlled by controlling the spraying parameters, and the drug is uniformly dispersed by spraying. The ultrasonic spraying process has adjustable and controllable parameters and good repeatability, and is suitable for industrial production.

Drawings

Fig. 1 is a schematic structural diagram of a multi-layer tectorial membrane drug-loaded airway stent.

Detailed Description

The present invention will be described in more detail with reference to the following examples and drawings.

Example 1

A double-layer tectorial membrane medicine-carrying airway stent comprises a stent body, a blank membrane and a medicine-carrying membrane. The stent body is of a metal porous net structure, the blank film is coated on the surface of the stent main body, and the drug-loaded film is coated on the surface of the blank film. The blank film is a silicon rubber film, and the composition of the drug-loaded film is shown in table 1:

TABLE 1

The preparation method of the double-layer film-covered drug-loaded airway stent comprises the following steps:

dissolving silicon rubber by using petroleum ether, wherein the solution viscosity is 10.28 cp; the bare metal stent was immersed in the silicone rubber solution for 10 minutes, and the immersion was repeated 3 times. Taking out and drying in an electric heating air blast drying oven at 120 ℃ to form a layer of blank film on the surface of the bracket;

according to the prescription amount specified in table 1, dissolving the silicone rubber by using petroleum ether, mixing the paclitaxel and the povidone K90, dissolving by using ethanol, and uniformly mixing the two solutions to obtain a mixed solution containing the paclitaxel, the povidone K90 and the silicone rubber; the viscosity of the mixed solution was measured (the measured value of viscosity is shown in Table 2).

The mixed solution is sprayed on the surface of a blank film by ultrasonic spraying equipment, the spraying flow is 0.4ml/min, the power of an ultrasonic spray head is 1W, the moving speed is 3mm/s, the rotating speed is 2r/s, the ultrasonic frequency is 120kHz, and the spraying times are 12 times. After the solvent is volatilized, the mixture is dried in an electrothermal blowing dry box for 2 to 4 hours at the temperature of between 60 and 80 ℃, and a drug-loaded film is formed on the surface of the blank film.

And after the preparation of the stent is finished, taking any five points on the drug-loaded membrane for drug content determination, and calculating the drug content RSD.

And after the preparation of the stent is finished, taking any five points on the drug-loaded membrane for membrane thickness measurement, and calculating the thickness RSD.

The scaffolds were placed in a centrifuge tube and shaken at 37 ℃ and 75r/min in an air constant temperature shaker using 40mL of Phosphate Buffered Saline (PBS) containing 1% sodium dodecyl sulfate as the release medium. 1mL of release medium was removed at the time specified and supplemented with the same volume of fresh PBS solution. The drug release test was carried out by high performance liquid chromatography using a sample solution obtained by filtration through a 0.45 μm tetrafluoroethylene filter. Calculate the drug release rate of 2h, 1d, 7d, 14d and 29 d.

Examples 1-1 to 1-4 the solution viscosity, drug-loaded film thickness RSD, drug content RSD, and drug release are shown in Table 2:

TABLE 2

As can be seen from the data in Table 2, the effect of the drug active ingredient in the range of 0.2-5% is the best (the uniformity of the drug content is better, the uniformity of the film thickness is better, and the drug release curve is in accordance with the expectation), when the content of the drug active ingredient is 10% and 18%, the uniformity of the film thickness is poorer, and the drug release has a slightly too fast burst release phenomenon (the release degree is too high in 2 hours).

Example 2

A double-layer tectorial membrane medicine-carrying airway stent comprises a stent body, a blank membrane and a medicine-carrying membrane. The stent body is of a metal porous net structure, the blank film is coated on the surface of the stent main body, and the drug-loaded film is coated on the surface of the blank film. The blank film is a silicon rubber film, and the composition of the drug-loaded film is shown in table 3:

TABLE 3

Components	2-1	2-2	2-3	2-4	2-5
						Paclitaxel/g	0.10	0.10	0.10	0.10	0.10
Povidone K90/g	0.06	0.20	0.30	0.30	0.50
						Silicone rubber/g	1.84	1.70	1.60	1.60	1.40

Note: 2-4 povidone K90 was replaced with polyethylene glycol 1000.

according to the prescription amount specified in table 3, dissolving the silicone rubber by using petroleum ether, mixing the paclitaxel and the povidone K90 (or polyethylene glycol 1000) and dissolving by using ethanol, and uniformly mixing the two solutions to obtain a mixed solution containing the paclitaxel, the povidone K90 (or polyethylene glycol 1000) and the silicone rubber; the viscosity of the mixed solution was measured (the viscosity values are shown in Table 4).

The solution viscosity, the drug-loaded film thickness RSD, the drug content RSD and the drug release rate are shown in the table 4 in the specification of 2-1-2-5:

TABLE 4

As can be seen from the results in Table 4, the effect is optimal when the content of the pore-forming agent is 10-25% (the uniformity of the drug content is good, the uniformity of the film thickness is good, and the drug release curve is in line with the expectation). When the content of the pore-forming agent is 3%, the total release degree of the medicine is lower.

Example 3

A double-layer tectorial membrane medicine-carrying airway stent comprises a stent body, a blank membrane and a medicine-carrying membrane. The stent body is of a metal porous net structure, the blank film is coated on the surface of the stent main body, and the drug-loaded film is coated on the surface of the blank film. The blank film is a silicon rubber film, and the medicine-carrying film comprises the following components: 0.10g of paclitaxel, 0.30g of povidone K90 and 1.60g of silicon rubber.

according to the prescription amount, the silicone rubber is dissolved by petroleum ether, the paclitaxel and the povidone K90 are mixed and dissolved by ethanol, and the two solutions are uniformly mixed to obtain a mixed solution containing the paclitaxel, the povidone K90 and the silicone rubber; the viscosity of the mixed solution was measured and found to be 1.29 cp.

The mixed solution is sprayed on the surface of a blank film by ultrasonic spraying equipment, the spraying flow is 0.4ml/min, the power of an ultrasonic spray head is 1W, the moving speed is 5mm/s, the rotating speed is 2r/s, the ultrasonic frequency is 120kHz, and the spraying times are 12 times. After the solvent is volatilized, the mixture is dried in an electrothermal blowing dry box for 2 to 4 hours at the temperature of between 60 and 80 ℃, and a drug-loaded film is formed on the surface of the blank film.

The drug-loaded film thickness RSD is 3.14%, the drug content RSD is 2.49%, and the drug release rate of 2h, 1d, 7d, 14d and 29d is 13.90%, 30.98%, 45.81%, 60.04% and 68.40%.

Example 4

according to the prescription amount, the silicone rubber is dissolved by petroleum ether, the paclitaxel and the povidone K90 are mixed and dissolved by ethanol, and the two solutions are uniformly mixed to obtain a mixed solution containing the paclitaxel, the povidone K90 and the silicone rubber; the viscosity of the mixed solution was measured and found to be 1.27 cp.

The mixed solution is sprayed on the surface of a blank film by ultrasonic spraying equipment, the spraying flow is 0.4ml/min, the power of an ultrasonic spray head is 1W, the moving speed is 3mm/s, the rotating speed is 4r/s, the ultrasonic frequency is 120kHz, and the spraying times are 12 times. After the solvent is volatilized, the mixture is dried in an electrothermal blowing dry box for 2 to 4 hours at the temperature of between 60 and 80 ℃, and a drug-loaded film is formed on the surface of the blank film.

The drug-loaded film thickness RSD is 3.56%, the drug content RSD is 3.88%, and the drug release rate of 2h, 1d, 7d, 14d and 29d is 16.40%, 31.20%, 40.91%, 52.45% and 64.72%.

Example 5

A double-layer tectorial membrane medicine-carrying airway stent comprises a stent body, a blank membrane and a medicine-carrying membrane. The stent body is of a metal porous net structure, the blank film is coated on the surface of the stent main body, and the drug-loaded film is coated on the surface of the blank film. The blank film is a high polymer material film, and the drug-loaded film comprises the following components: 0.10g of paclitaxel, 0.30g of povidone K90 and 1.60g of high polymer material; wherein the high molecular materials are respectively silicon rubber, polytetrafluoroethylene, polyurethane or ethylene-vinyl acetate copolymer.

respectively dissolving the high molecular materials by using corresponding solvents, wherein the solution viscosity is about 10.28 cp; the bare metal stent was immersed in the polymer material solution for 10 minutes, and the immersion was repeated 3 times. Taking out and drying in an electric heating air blast drying oven at 120 ℃ to form a layer of blank film on the surface of the bracket;

according to the prescription amount, dissolving the high polymer material by using a corresponding solvent, mixing the paclitaxel and the povidone K90, dissolving by using ethanol, and uniformly mixing the two solutions to obtain a mixed solution containing the paclitaxel, the povidone K90 and the high polymer material; the viscosity of the mixed solution was measured (the viscosity measurement value is shown in Table 5).

Examples 5-1 to 5-4 the solution viscosity, drug-loaded film thickness RSD, drug content RSD, and drug release are shown in Table 5:

TABLE 5

Comparative example 1

A double-layer tectorial membrane medicine-carrying airway stent comprises a stent body, a blank membrane and a medicine-carrying membrane. The stent body is of a metal porous net structure, the blank film is coated on the surface of the stent main body, and the drug-loaded film is coated on the surface of the blank film. The blank film is a silicon rubber film, and the medicine-carrying film comprises the following components: 0.65g of paclitaxel, 0.30g of povidone K90 and 1.05g of silicone rubber.

according to the prescription amount, the silicone rubber is dissolved by using petroleum ether, the paclitaxel and the povidone K90 are mixed and dissolved by using ethanol, and the two solutions are uniformly mixed to obtain a mixed solution containing the paclitaxel, the povidone K90 and the silicone rubber.

The mixed solution has flocculent precipitates and cannot be used for a spraying process.

Comparative example 2

according to the prescription amount, the silicone rubber is dissolved by petroleum ether, the paclitaxel and the povidone K90 are mixed and dissolved by ethanol, and the two solutions are uniformly mixed to obtain a mixed solution containing the paclitaxel, the povidone K90 and the silicone rubber; the viscosity of the mixed solution was measured to be 1.31 cp.

The mixed solution is sprayed on the surface of a blank film by ultrasonic spraying equipment, the spraying flow is 1.5ml/min, the power of an ultrasonic spray head is 1W, the moving speed is 3mm/s, the rotating speed is 2r/s, the ultrasonic frequency is 120kHz, and the spraying times are 12 times. In the spraying process, the hanging flow phenomenon appears on the surface of the bracket, and the bracket cannot be used.

Comparative example 3

The mixed solution is sprayed on the surface of a blank film by ultrasonic spraying equipment, the spraying flow is 0.4ml/min, the power of an ultrasonic spray head is 1W, the moving speed is 12mm/s, the rotating speed is 2r/s, the ultrasonic frequency is 120kHz, and the spraying times are 12 times. In the spraying process, the hanging flow phenomenon appears on the surface of the bracket, and the bracket cannot be used.

Comparative example 4

The mixed solution is sprayed on the surface of a blank film by ultrasonic spraying equipment, the spraying flow is 0.4ml/min, the power of an ultrasonic spray head is 1W, the moving speed is 3mm/s, the rotating speed is 12r/s, the ultrasonic frequency is 120kHz, and the spraying times are 12 times. In the spraying process, the hanging flow phenomenon appears on the surface of the bracket, and the bracket cannot be used.

Comparative example 5

In the prior art, a hot-pressing method is used for preparing a stent drug-loaded membrane, and the drug-loaded membrane comprises the following components: 0.10g of paclitaxel, 0.30g of povidone K90 and 1.60g of silicon rubber. After the preparation is finished, any five points on the drug-loaded membrane are taken for drug content determination, and the drug content RSD is 9.20%.

In the prior art, a hot pressing method is used for preparing the stent drug-loaded membrane, after the preparation is finished, any five points on the drug-loaded membrane are taken for measuring the thickness of the membrane, and the RSD is 5.42%.

Claims

1. A multi-layer film-coated drug-loaded stent is characterized by comprising a stent body, a blank film and a drug-loaded film, wherein the blank film is coated on the surface of the stent body, and the drug-loaded film is coated on the surface of the blank film; wherein the drug-loaded membrane contains a drug active component, a pore-forming agent and a second non-biodegradable high molecular material.

2. The multilayer coated drug-loaded stent of claim 1, wherein the blank membrane is a first non-biodegradable polymeric material;

3. The multilayer film-coated drug-loaded stent according to claim 1 or 2, wherein the content of the pharmaceutically active ingredient in the drug-loaded film is 0.12-30.24 wt.%; the content of the pore-forming agent is 0.11-45.98 wt.%; the content of the second non-biodegradable high polymer material is 50.21-99.40 wt.%.

4. The multilayer coated drug-loaded scaffold according to any of claims 1 to 3, wherein the amount of pore-forming agent is 0.30-25.12 wt.%, preferably 10.00-25.00 wt.%; preferably, the content of the pharmaceutically active ingredient is 0.21-15.73 wt.%, preferably 0.20-5.00 wt.%.

5. The multi-layer coated drug-loaded scaffold of any one of claims 1-4, wherein the drug-loaded membrane consists of a pharmaceutically active ingredient, a pore-forming agent and a second non-biodegradable polymeric material.

6. The multilayer coated stent according to any one of claims 1 to 5, wherein the pharmaceutically active ingredient is selected from the group consisting of antineoplastic drugs selected from rapamycin, paclitaxel derivatives, Evimos, tacrolimus, emodin, heparin, hirudin, etc., preferably paclitaxel or rapamycin.

7. The multi-layered coated drug-loaded scaffold according to any of claims 1 to 6, wherein the pore-forming agent is selected from one or more of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) and Hydroxypropylmethylcellulose (HPMC), preferably PVP;

8. The multilayer film-coated drug-loaded stent according to any one of claims 1 to 7, wherein the thickness of the blank film or drug-loaded film is 10-500 μm; preferably, the thickness of the blank film or the drug-loaded film is 15-150 μm;

preferably, the stent body is a metal porous mesh structure.

9. A method of making a multilayer stent graft of any one of claims 1 to 8, the method comprising:

preferably, in the step b), the viscosity is 1.00-10.00 cp;

10. Use of a multilayer stent graft according to claims 1 to 8, wherein the stent is for luminal narrowing and obstruction due to lesions;