CN110882422B

CN110882422B - Airway stent and application thereof

Info

Publication number: CN110882422B
Application number: CN201911422776.1A
Authority: CN
Inventors: 夏佩佩; 邢若豪; 晏伟; 魏征
Original assignee: Puyi Shanghai Biotechnology Co ltd
Current assignee: Puyi Shanghai Biotechnology Co ltd
Priority date: 2019-12-31
Filing date: 2019-12-31
Publication date: 2022-02-01
Anticipated expiration: 2039-12-31
Also published as: CN110882422A; CN113941036A; CN113941036B

Abstract

The invention provides an airway stent and application thereof, wherein the airway stent comprises a silicon rubber matrix and a medicament, and the medicament is dispersed in the silicon rubber matrix; the airway stent is implanted into an airway, the release condition of the drug can be controlled, and the airway stent contains the drug, so that the airway stent has a good treatment effect on airway injury and can be used for expanding a narrow airway and inhibiting airway restenosis.

Description

Airway stent and application thereof

Technical Field

The invention belongs to the field of medical equipment, and relates to an airway stent and application thereof.

Background

Airway stenosis is a life-threatening disease caused by congenital or diseases such as infection, airway tumor, trauma, endobronchial tuberculosis, etc., and clinically manifested as cough, expectoration, dyspnea and even respiratory failure. The tracheal stent is an interventional treatment means for various benign or malignant airway stenosis, can relieve tracheal obstruction symptoms of patients, plays a role in temporary tracheal expansion or support, and provides opportunities for subsequent further treatment (radiotherapy, chemotherapy and the like).

There are data indicating that 30% of lung cancer patients are accompanied by central airway narrowing. Central airway stenosis has become one of the common emergencies in patients with advanced lung cancer, severely affects the respiratory function of the patients, causes the quality of life to be reduced, and affects the anti-tumor treatment of the patients. Although the airway naked stent used clinically can be used for relieving corresponding symptoms, the regrowth of the tumor is frequently caused due to the lack of local treatment of the tumor; and although external radiotherapy provides a great help after stent implantation, 37% of patients are unable to receive radiotherapy, and over one third of patients die from tumor growth-related asphyxia.

At present, silicone is better for treating the airway stenosis, and a silicone bracket is expensive and has no obvious treatment effect on the severe airway stenosis.

Therefore, there is a need for a new type of airway stent.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide an airway stent and an application thereof, the airway stent is implanted into an airway, the release condition of a medicament can be controlled, the medicament contained in the airway stent has a better treatment effect on airway injury, and the airway stent can be used for expanding a narrow airway and inhibiting the restenosis of the airway.

One of the objects of the present invention is to provide an airway stent, which comprises a silicon rubber matrix and a drug, wherein the drug is dispersed in the silicon rubber matrix.

In the invention, the airway stent has the treatment effect with low dosage and high efficiency, has longer drug release period and better sustained release capability, and has better treatment effect on the damaged airway.

In the present invention, the silicone rubber base includes a silicone rubber holder.

In the present invention, the drug is dispersed inside the silicone rubber stent.

In the present invention, when the silicone rubber base includes only the silicone rubber stent, the drug is uniformly dispersed inside the silicone rubber stent; the medicine can be uniformly dispersed in the whole silicon rubber bracket or a certain specific position in the silicon rubber bracket, can be used for integral treatment and local treatment, and can be used for targeted treatment according to the wound condition during local treatment; when the airway stent is implanted into the airway, the medicine can be released into the airway, and the damaged airway has a better treatment effect.

In the invention, the silicon rubber substrate also comprises a silicon rubber film, the silicon rubber film is arranged on the surface of the silicon rubber stent, and the medicine is dispersed in the silicon rubber film.

In the invention, the silicon rubber substrate also comprises a silicon rubber film, the silicon rubber film is arranged on the surface of the silicon rubber stent, and the medicine is dispersed in the silicon rubber stent and the silicon rubber film.

In the invention, when the silicon rubber substrate also comprises a silicon rubber film, the medicine can be distributed in the silicon rubber film, or the medicine can be dispersed in the silicon rubber stent and the silicon rubber film; the medicine can be uniformly dispersed in the whole silicon rubber matrix, also can be uniformly dispersed in a certain specific part in the silicon rubber matrix, can be used for the integral treatment of an airway and also can be used for the local treatment, and when the local treatment is carried out, the targeted treatment can be carried out according to the specific wound condition.

In the present invention, the silicone rubber stent and the silicone rubber film are bonded together by an adhesive.

In the present invention, the silicone rubber stent and the silicone rubber membrane are cured together in a semi-solid state.

In the present invention, the particle size of the drug dispersed in the silicone rubber film is 500-10000 mesh, for example, 500 mesh, 1000 mesh, 1500 mesh, 2000 mesh, 2500 mesh, 3000 mesh, 3500 mesh, 4000 mesh, 4500 mesh, 5000 mesh, 5500 mesh, 6000 mesh, 6500 mesh, 7000 mesh, 7500 mesh, 8000 mesh, 8500 mesh, 9000 mesh, 9500 mesh, 10000 mesh, etc., preferably 1000-8000 mesh.

The invention controls the release rate of the medicament by controlling the mesh number of the medicament, thereby controlling the drug effect and the medicament release period. When the mesh number of the medicine is too low, the larger the particle size of the medicine is, the more difficult the medicine is to dissolve out, thereby affecting the treatment effect; when the mesh number of the drug is too high, the particle size of the drug is small and the drug is easy to dissolve out, which causes too high blood concentration and other side effects.

In the present invention, a drug is also dispersed in the silicone rubber stent.

In the present invention, the particle size of the drug dispersed in the silicone rubber stent is 1000-8000 meshes, such as 1000 meshes, 1500 meshes, 2000 meshes, 2500 meshes, 3000 meshes, 3500 meshes, 4000 meshes, 4500 meshes, 5000 meshes, 5500 meshes, 6000 meshes, 6500 meshes, 7000 meshes, 7500 meshes, 8000 meshes, and the like.

In the invention, the release rate of the medicament is controlled by controlling the mesh number of the medicament in the silicon rubber stent, so that the medicament effect and the medicament testing period are controlled; when the silicon rubber substrate only comprises the silicon rubber stent, the medicine is required to be controlled within a proper mesh range, so that the medicine has a proper dissolution rate and does not cause side reaction to a human body; when the silicon rubber substrate comprises the silicon rubber stent and the silicon rubber film, the release rate of the medicines in the silicon rubber stent and the silicon rubber film needs to be controlled, so that the medicines in the silicon rubber stent and the silicon rubber film are matched for use, and a better treatment effect is exerted.

In the present invention, the amount of drug in one of the airway stents is 2-200mg, such as 2mg, 20mg, 50mg, 80mg, 100mg, 120mg, 150mg, 170mg, 200mg, etc.

In the invention, the drug in the airway stent releases 5-150 mug of drug per day, such as 5 mug, 10 mug, 20 mug, 50 mug, 80 mug, 100 mug, 120 mug, 150 mug and the like, reaches the threshold of action for at least 7 days, thereby obtaining a slow release system capable of controlling the release rate and the release period.

In the invention, the shape of the silicon rubber stent is a tubular structure.

The specific shape of the silicone rubber support is not specifically limited, and the silicone rubber support can be adjusted by a person skilled in the art according to actual needs.

In the present invention, the thickness of the tubular structure is 0.5-2.0mm, such as 0.5mm, 0.6mm, 0.7mm, 0.8mm, 0.9mm, 1mm, 1.1mm, 1.2mm, 1.3mm, 1.4mm, 1.5mm, 1.6mm, 1.7mm, 1.8mm, 1.9mm, 2mm, etc.

In the invention, the wall thickness of the control tube body is 0.5-2mm, and when the silicon rubber substrate only comprises the silicon rubber stent, the drug is distributed in the silicon rubber stent, so that the release rate of the drug can be better controlled; when the wall thickness of the tube body is too low, the tube body is easy to deform, so that a channel is narrowed, and explosive release of the medicine can be generated; when the wall thickness of the tube body is too thick, the medicine can not be released; when the silicon rubber substrate also comprises a silicon rubber film, when the medicine is dispersed in the silicon rubber film, the wall thickness of the tube body is too low, the tube body is easy to deform, and the channel is narrowed; when the medicine is dispersed in the silicone rubber stent and the silicone rubber film, the wall thickness of the tube body is too low, so that the tube body is easy to deform, the channel is narrowed, and when the thickness of the tube body is too thick, the medicine can be difficult to release.

In the present invention, the hardness of the silicone rubber stent is 40 to 90A, such as 40A, 45A, 50A, 55A, 60A, 65A, 70A, 75A, 80A, 85A, 90A, and the like.

The hardness of the silicone rubber support is 40-90A, so that a better supporting effect can be achieved; when the thickness of the silicon rubber support is too low, the tube body is easy to deform, so that the channel is narrowed; when the hardness of the silicone rubber stent is too high, the airway may be damaged.

In the present invention, the thickness of the silicone rubber film is 0.05 to 1mm, for example, 0.05mm, 0.1mm, 0.15mm, 0.2mm, 0.25mm, 0.3mm, 0.35mm, 0.4mm, 0.45mm, 0.5mm, 0.55mm, 0.6mm, 0.65mm, 0.7mm, 0.75mm, 0.8mm, 0.85mm, 0.9mm, 0.95mm, 1mm, etc., preferably 0.1 to 0.5 mm.

In the invention, the thickness of the silicon rubber film is 0.05-1mm, so that the release rate of the medicament can be better controlled; when the thickness of the silicon rubber film is too low, the medicament can be burst; when the thickness of the silicone rubber film is too high, the drug is difficult to dissolve out, thereby affecting the therapeutic effect.

In the present invention, the silicone rubber film has a hardness of 30 to 60A.

In the invention, the hardness of the silicon rubber film is 30-60A, so that the air channel can be prevented from being damaged by the stent.

In the present invention, the drug includes any one or a combination of at least two of aspirin, salicylic acid, sodium salicylate, magnesium salicylate, diflunisal, salsalate, ibuprofen, indomethacin, flurbiprofen, phenoxyibuprofen, naproxen, piroxicam, phenylbutazone, fenbufen, carprofen, ketoprofen, diclofenac, ketorolac, tetrafluorofenamic acid, sulindac, tolmetin, celecoxib, aminoglycoside antibiotics, anti-adhesion and anti-scarring agents, macrolide antibiotics, cyclosporine a, berberine hydrochloride, paclitaxel, docetaxel, vinorelbine, elemene, or enalapril.

In the present invention, the aminoglycoside antibiotic includes any one or a combination of at least two of streptomycin, gentamicin, kanamycin, sisomicin, tobramycin, amikacin, netilmicin, nebivoxim, isepamicin, lividycin, micronomicin, paromomycin, neomycin, or aspartame.

In the present invention, the anti-adhesion and anti-scarring agent comprises glucocorticoid: triamcinolone acetonide, dexamethasone, betamethasone, cortisone, hydrocortisone, mometasone furoate, rimexolone, prednisone, prednisolone, methylprednisolone, triamcinolone, budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide, fluocinolone, clobetasol, halometasone, difloron diacetate, halomethasone or fluocinolone acetonide, or a combination of at least two thereof.

In the invention, the macrolide antibiotics comprise any one or combination of at least two of erythromycin and derivatives thereof, azithromycin, midecamycin and derivatives thereof, spiramycin and derivatives thereof, acetylspiramycin, tacrolimus, sirolimus, everolimus, amphotericin B, pentamycin, fidaxomicin, telithromycin or mitomycin.

In the present invention, the drug includes any one or a combination of at least two of rapamycin, mometasone furoate, mitomycin, or dexamethasone.

In the present invention, the silicone rubber film has a crosslinking density of 3000-8000g/mol, for example 3000g/mol, 3500g/mol, 4000g/mol, 4500g/mol, 5000g/mol, 5500g/mol, 6000g/mol, 6500g/mol, 7000g/mol, 7500g/mol, 8000g/mol, etc., preferably 4000-6000 g/mol.

In the present invention, the cross-linking density of the silicone rubber stent is 3000-8000g/mol, such as 3000g/mol, 3500g/mol, 4000g/mol, 4500g/mol, 5000g/mol, 5500g/mol, 6000g/mol, 6500g/mol, 7000g/mol, 7500g/mol, 8000g/mol, etc., preferably 5000-8000 g/mol.

In the invention, the crosslinking density refers to the number of effective network chains contained in the thermosetting elastomer per unit volume, and can represent the crosslinking degree of the elastomer. However, the crosslinking density affects the properties of the silicone rubber such as elastic modulus, breaking strength, elongation at break and the like, so that the crosslinking density in the above range has the best elasticity and slow release effect; when the medicine is uniformly dispersed in the silicon rubber support and the silicon rubber film, the release rate of the medicine is controlled by controlling the crosslinking density of the silicon rubber support and the silicon rubber film, and a better treatment effect is achieved by matching the medicine.

In the present invention, the silicone rubber film includes 60 to 90% by mass of silicone rubber (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, etc.), 4 to 39.8% by mass of a drug (e.g., 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 39.8%, etc.), 0.1 to 3% by mass of a crosslinking agent (e.g., 0.1%, 0.5%, 0.8%, 1%, 1.2%, 1.5%, 1.7%, 2%, 2.2%, 2.5%, 2.7%, 3%, etc.), and 0.1 to 3% by mass of a catalyst (e.g., 0.1%, 0.5%, 0.8%, 1%, 1.2%, 1.5%, 1.7%, 2%, 2.2%, 2.5%, 2.7%, 3%, etc.).

In the present invention, the silicone rubber comprises any one or a combination of at least two of a heat vulcanized silicone rubber, Dow Corning Silastic-382 medical grade silicone rubber, Dow Corning Q7 medical grade silicone rubber series, Dow Corning C6 medical grade silicone rubber series, or an implant grade MDX series.

In the present invention, the crosslinking agent includes hydrogen-containing silicone oil and/or hydrogen-containing siloxane.

In the present invention, the catalyst includes any one of a platinum complex, a ruthenium complex, or a rhodium complex, or a combination of at least two thereof.

In the present invention, the method for preparing the silicone rubber film comprises: and mixing the silicon rubber, the medicine, the cross-linking agent and the catalyst, and carrying out vulcanization crosslinking to obtain the silicon rubber film.

In the present invention, the silicone rubber stent includes 60 to 99.8% by mass of silicone rubber (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, 99.8%, etc.), 0 to 39.8% of a drug (e.g., 0%, 3%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 27%, 30%, 32%, 35%, 37%, 39.8%, etc.), 0.1 to 3% of a crosslinking agent (e.g., 0.1%, 0.5%, 0.8%, 1%, 1.2%, 1.5%, 1.7%, 2%, 2.2%, 2.5%, 2.7%, 3%, etc.), and 0.1 to 3% of a catalyst (e.g., 0.1%, 0.5%, 0.8%, 1%, 1.2%, 1.5%, 1.7%, 2.5%, 2.8%, 3%, etc.)%, and 0.1 to 3% by mass of a catalyst (e.1 to 3%), 2.7%, 3%, etc.).

In the invention, the silicon rubber for the silicon rubber stent comprises any one or the combination of at least two of hot vulcanized silicon rubber, room temperature vulcanized silicon rubber, low temperature vulcanized silicon rubber, Dow Corning Silastic-382 medical grade silicon rubber, Dow Corning Q7 medical grade silicon rubber series or implantation grade MDX series.

In the invention, the preparation method of the silicone rubber stent comprises the following steps: and mixing the silicon rubber, a cross-linking agent and a catalyst, and carrying out vulcanization crosslinking to obtain the silicon rubber support.

In the present invention, the period of drug release in the airway stent is 15 days to 12 months, such as 15 days, 1 month, 1.5 months, 2 months, 2.5 months, 3 months, 3.5 months, 4 months, 4.5 months, 5 months, 5.5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, etc.

In the present invention, the release period of the drug in the airway stent is 1-3 months, such as 1 month, 1.2 months, 1.5 months, 1.8 months, 2 months, 2.2 months, 2.5 months, 2.7 months, 3 months, etc.

The second purpose of the invention is to provide the application of the airway stent in a drug sustained release system.

Compared with the prior art, the invention has the following beneficial effects:

the airway stent is implanted into an airway, the release condition of the drug can be controlled, and the drug contained in the airway stent has a good treatment effect on airway injury and can be used for expanding a narrow airway and inhibiting the restenosis of the airway.

Drawings

FIG. 1 is a schematic view showing the structure of an airway stent in example 1;

FIG. 2 is a graph showing drug release profiles of airway stents in example 1

FIG. 3 is a schematic view showing the structure of an air duct support in example 4;

fig. 4 is a sectional view of a portion (with a drug film) of fig. 3.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

In a specific embodiment, all of the starting materials are commercially available,

hydroxyl silicone oil: model PMX-0930, sourced Dow Corning;

platinum catalyst: type 5000PPM, derived from Eucalyptus globulus Labill.

Example 1

The present embodiment provides an airway stent, as shown in fig. 1, the airway stent (bronchial stent) is a Y-shaped tubular structure; the airway stent comprises a silicon rubber stent and a silicon rubber film positioned on the surface of the silicon rubber stent, wherein the silicon rubber film comprises a silicon rubber film and a medicament dispersed in the silicon rubber film; wherein the cross-linking density of the silicone rubber is 5000 g/mol; the medicine is mometasone furoate, and the particle size of the medicine is 4000 meshes; the thickness of the tubular structure of the silicon rubber bracket is 0.8 mm; the thickness of the silicone rubber film was 0.2 mm.

The embodiment also provides a preparation method of the airway stent, which comprises the following steps:

(1) taking 99.8 parts of heat-vulcanized silicone rubber, 0.5 part of hydroxyl silicone oil and 0.3 part of platinum catalyst, fully and uniformly mixing, and then vulcanizing and molding in a mold to obtain a silicone rubber support with the wall thickness of 0.8 mm;

(2) taking 95 parts of heat-vulcanized silicone rubber, 3.2 parts of mometasone furoate (the particle size is 4000 meshes), 1 part of hydroxyl silicone oil and 0.8 part of platinum catalyst, fully and uniformly mixing, and then vulcanizing and molding in a mold to obtain a silicone rubber film with the thickness of 0.2 mm;

(3) and (3) adhering the silicon rubber film obtained in the step (2) to the outer surface of the silicon rubber support obtained in the step (1) by using glue to obtain the air passage support.

The maximum amount of drug dissolved in the first 3 days is 89 mug/d, the subsequent gradual and gradual decline of the maximum amount of drug dissolved in the first 3 days is 23 mug/d, d is an abbreviation of unit day, and the meaning of d is the same as that in the subsequent description, and the details are not repeated.

Taking a new Zealand test rabbit for testing, scratching the air passage in an operation mode before implanting the air passage to cause a wound surface, and suturing and binding. After 30 days, the MSCT observes the stenosis degree, and the test results are shown in the table 1:

TABLE 1

Wherein D1 is the maximum transverse diameter of the narrow part of the airway, and D2 is the longitudinal diameter perpendicular to D1; d3 is the maximum transverse diameter of the cartilage ring in the normal airway, D4 is the longitudinal diameter of the cartilage ring perpendicular to D3;

s (stenosis rate) ([ 1- (D1 × D2)/(D3 × D4) ]) 100%;

as can be seen from Table 1, the mean stenosis rate of the airways before the implantation of the airway stent is 70.7%, and the mean stenosis rate after 30 days of implantation is 61.5%, which indicates that the airway stent has significant effect after the implantation.

The physical properties of the airway stent used in the present embodiment were tested according to the test method of standard GB/T528.1-2009, which shows that: the hardness of the silicone rubber stent is 60A, and the hardness of the silicone rubber film is 35A.

Example 2

The embodiment provides an airway stent, which comprises a silicon rubber stent and a silicon rubber film positioned on the surface of the silicon rubber stent, wherein the silicon rubber film comprises a silicon rubber film and a medicament dispersed in the silicon rubber film; wherein the cross-linking density of the silicone rubber is 4000 g/mol; the medicine is sirolimus, and the grain size of the medicine is 500 meshes; the shape of the silicon rubber support is a straight tubular structure, and the thickness of the tubular structure is 0.5 mm; the thickness of the silicone rubber film was 0.5 mm.

(1) taking 99.8 parts of heat-vulcanized silicone rubber, 0.1 part of hydroxyl silicone oil and 0.1 part of platinum catalyst, fully and uniformly mixing, and then semi-curing and molding in a mold to obtain a semi-cured silicone rubber support with the wall thickness of 0.5 mm;

(2) taking 90 parts of heat-vulcanized silicone rubber, 4 parts of mometasone furoate (the particle size is 500 meshes), 3 parts of hydroxyl silicone oil and 3 parts of platinum catalyst, fully and uniformly mixing, and then performing semi-curing molding in a mold to obtain a semi-cured silicone rubber film with the thickness of 0.5 mm;

(3) and (3) wrapping the semi-cured silicon rubber film obtained in the step (2) on the outer surface of the semi-cured silicon rubber support obtained in the step (1), and putting the semi-cured silicon rubber film into a mold to be cured into a whole, so as to obtain the air duct support.

The sample is dissolved in a simulated solution at 37 ℃ by a drug dissolution tester, and the amount of the dissolved drug is tested by HPLC, so that the maximum amount of the drug dissolved in the first 3 days is 45 mug/d within 30 days, the maximum amount of the drug dissolved in the later days gradually becomes stable and slow, and the average release degree within 30 days is 19 mug/d.

In the same manner as in example 1, before implantation into the airway, the airway was scratched by surgery to cause a wound surface, and bandaged with suture. After 30 days, the MSCT observes the degree of stenosis, and then the results show that: the average stenosis rate of the airway before the implantation of the airway stent is 71.6 percent, and the average stenosis rate after the implantation for 30 days is 63.7 percent, which shows that the airway stent has obvious effect after the implantation.

The physical properties of the airway stent used in this example were tested according to the test method of example 1, and it was found that: the hardness of the silicone rubber stent is 50A, and the hardness of the silicone rubber film is 40A.

Example 3

The embodiment provides an airway stent, which comprises a silicon rubber stent and a silicon rubber film positioned on the surface of the silicon rubber stent, wherein the silicon rubber film comprises a silicon rubber film and a medicament dispersed in the silicon rubber film; wherein the cross-linking density of the silicon rubber is 6000 g/mol; the medicine is mometasone furoate, and the particle size of the medicine is 1000 meshes; the shape of the silicon rubber support is a straight tubular structure, and the thickness of the tubular structure is 2 mm; the thickness of the silicone rubber film was 0.1 mm.

(1) taking 94 parts of heat-vulcanized silicone rubber, 3 parts of hydroxyl silicone oil and 3 parts of platinum catalyst, fully mixing uniformly, and then vulcanizing and molding in a mold to obtain a silicone rubber support with the wall thickness of 2 mm;

(2) taking 60 parts of heat-vulcanized silicone rubber, 34 parts of mometasone furoate (the particle size is 1000 meshes), 3 parts of hydroxyl silicone oil and 3 parts of platinum catalyst, fully and uniformly mixing, and then vulcanizing and molding in a mold to obtain a silicone rubber film with the thickness of 0.1 mm;

The drug dissolution tester is used for dissolving the drug in a simulated solution at 37 ℃ and testing the amount of the dissolved drug by HPLC, so that the maximum drug dissolution amount in the first 3 days is 135 mug/d within 30 days, the maximum drug dissolution amount in the later days gradually becomes stable and slow, and the average release rate in 30 days is 60 mug/d.

In the same manner as in example 1, before implantation into the airway, the airway was scratched by surgery to cause a wound surface, and bandaged with suture. After 30 days, the MSCT observes the degree of stenosis, and then the results show that: the average stenosis rate of the airway before the implantation of the airway stent is 73.6 percent, and the average stenosis rate after the implantation for 30 days is 60.5 percent, which shows that the airway stent has obvious effect after the implantation.

The physical properties of the airway stent used in this example were tested according to the test method of example 1, and it was found that: the hardness of the silicone rubber stent is 80A, and the hardness of the silicone rubber film is 30A.

Example 4

The embodiment provides an airway stent, as shown in fig. 3 and 4, the airway stent comprises a silicon rubber stent 1 and a silicon rubber film 2 positioned on the local surface of the silicon rubber stent, wherein the silicon rubber film comprises a silicon rubber film and a medicament dispersed in the silicon rubber film; wherein the cross-linking density of the silicone rubber is 3000 g/mol; the medicine is mometasone furoate, and the particle size of the medicine is 500 meshes; the shape of the silicon rubber support is a straight tubular structure, and the thickness of the tubular structure is 1.5 mm; the thickness of the silicone rubber film was 1 mm.

(1) taking 95 parts of heat-vulcanized silicone rubber, 2 parts of hydroxyl silicone oil and 3 parts of platinum catalyst, fully mixing uniformly, and vulcanizing and molding in a mold to obtain a silicone rubber support with the wall thickness of 1.5 mm;

(2) taking 80 parts of heat-vulcanized silicone rubber, 14 parts of mometasone furoate (the particle size is 500 meshes), 3 parts of hydroxyl silicone oil and 3 parts of platinum catalyst, fully and uniformly mixing, and then vulcanizing and molding in a mold to obtain a silicone rubber film with the thickness of 1 mm;

(3) and (3) adhering the silicon rubber film obtained in the step (2) to the outer surface of the part of the silicon rubber stent obtained in the step (1) by using glue to obtain the airway stent with a part of the medicine.

The sample is dissolved in PBS solution at 37 ℃ by a drug dissolution tester, and the amount of the dissolved drug is tested by HPLC, so that the maximum amount of the drug dissolved in the first 3 days is 57 mug/d within 30 days, the maximum amount gradually becomes stable and slow, and the average release degree within 30 days is 22 mug/d.

The physical properties of the airway stent used in this example were tested according to the test method of example 1, and it was found that: the hardness of the silicone rubber stent was 45A, and the hardness of the silicone rubber membrane was 38A.

Example 5

The embodiment provides an airway stent, which comprises a silicon rubber stent and a silicon rubber film positioned on the surface of the silicon rubber stent, wherein the silicon rubber film comprises a silicon rubber film and a medicament dispersed in the silicon rubber film; wherein the cross-linking density of the silicon rubber is 8000 g/mol; the medicine is mometasone furoate, and the particle size of the medicine is 10000 meshes; the shape of the silicon rubber support is a straight tubular structure, and the thickness of the tubular structure is 0.8 mm; the thickness of the silicone rubber film was 0.05 mm.

(1) taking 98 parts of heat-vulcanized silicone rubber, 1 part of hydroxyl silicone oil and 1 part of platinum catalyst, fully and uniformly mixing, and then vulcanizing and molding in a mold to obtain a silicone rubber support with the wall thickness of 0.8 mm;

(2) taking 70 parts of heat-vulcanized silicone rubber, 28 parts of mometasone furoate (the particle size is 10000 meshes), 1 part of hydroxyl silicone oil and 1 part of platinum catalyst, fully and uniformly mixing, and then vulcanizing and molding in a mold to obtain a silicone rubber film with the thickness of 0.05 mm;

The drug dissolution tester is used for dissolving the drug in a simulated solution at 37 ℃ and testing the amount of the dissolved drug by HPLC, so that the maximum drug dissolution amount in the first 3 days is 128 mug/d within 30 days, the maximum drug dissolution amount gradually becomes stable and slow, and the average release rate in 30 days is 57 mug/d.

The physical properties of the airway stent used in this example were tested according to the test method of example 1, and it was found that: the hardness of the silicone rubber stent is 65A, and the hardness of the silicone rubber film is 30A.

Example 6

The difference from the example 4 is that the aspirin medicine is uniformly dispersed in the silicon rubber stent, and the grain diameter of the medicine is 1000 meshes; the preparation method of the silicon rubber support comprises the following steps of (1) taking 92 parts of heat-vulcanized silicon rubber, 3 parts of aspirin, 2 parts of hydroxyl silicone oil and 3 parts of platinum catalyst, fully mixing uniformly, and then vulcanizing and molding in a mold to obtain the silicon rubber support with the wall thickness of 1.5 mm;

(3) and (3) adhering the silicon rubber film obtained in the step (2) to the outer surface of the part of the silicon rubber support obtained in the step (1) by using glue to obtain two air passage supports with the medicines.

The sample is subjected to drug dissolution in a simulated solution at 37 ℃ by a drug dissolution tester, and the amount of the dissolved drug is tested by HPLC, so that the maximum dissolution amount of the drug (mometasone furoate) in the first 3 days is 60 mug/d within 30 days, the maximum dissolution amount gradually and steadily decreases in the later period, and the average release degree within 30 days is 25 mug/d; the maximum aspirin dissolution amount in the first 3 days is 42 mug/d, the aspirin dissolution amount gradually becomes stable and slow, and the average release rate in 30 days is 16 mug/d; .

The physical properties of the airway stent used in this example were tested according to the test method of example 4, and it can be seen that: the hardness of the silicone rubber stent is 48A, and the hardness of the silicone rubber film is 40A.

Example 7

The embodiment provides an airway stent, which comprises a silicon rubber stent and a medicament uniformly dispersed in the silicon rubber stent; wherein the cross-linking density of the silicon rubber bracket is 6000g/mol, the medicine is mometasone furoate, and the grain size of the medicine is 4000 meshes; the shape of the silicon rubber support is a tubular structure, and the thickness of the tubular structure is 1.5 mm.

taking 75 parts of heat-vulcanized silicone rubber, 3 parts of hydroxyl silicone oil, 2 parts of platinum catalyst and 20 parts of medicine, fully and uniformly mixing, and then vulcanizing and molding in a mold to obtain the silicone rubber support with the wall thickness of 1.5 mm.

The drug dissolution tester is used for dissolving the drug in a simulated solution at 37 ℃ and testing the amount of the dissolved drug by HPLC, so that the maximum drug dissolution amount in the first 3 days is 109 mug/d within 30 days, the maximum drug dissolution amount gradually becomes stable and slow, and the average release rate in 30 days is 47 mug/d.

In the same manner as in example 1, before implantation into the airway, the airway was scratched by surgery to cause a wound surface, and bandaged with suture. After 30 days, the MSCT observes the degree of stenosis, and then the results show that: the average stenosis rate of the airway before the implantation of the airway stent is 72.3 percent, and the average stenosis rate after the implantation for 30 days is 60.9 percent, which shows that the airway stent has obvious effect after the implantation.

The physical properties of the airway stent used in this example were tested according to the test method of example 1, and it was found that: the hardness of the silicone rubber stent was 70A.

Comparative example 1

The difference from example 1 is only that the particle size of the drug is 200 mesh, and the rest of the composition and the preparation method are the same as example 1.

The sample is dissolved in a simulated solution at 37 ℃ by a drug dissolution tester, and the amount of the dissolved drug is tested by HPLC, so that the maximum amount of the drug dissolved in the first 3 days is 32 mug/d within 30 days, the maximum amount of the drug dissolved in the later days gradually becomes stable and slow, and the average release degree within 30 days is 4 mug/d.

In the same manner as in example 1, before implantation into the airway, the airway was scratched by surgery to cause a wound surface, and bandaged with suture. After 30 days, the MSCT observes the degree of stenosis, and then the results show that: the average stenosis rate of the airway before the implantation of the airway stent is 70.1 percent, and the average stenosis rate after the implantation for 30 days is 68.2 percent, which indicates that the airway stent has no significant effect after the implantation.

It is understood from the comparison between example 1 and comparative example 1 that when the mesh number of the drug is too low, the drug particles become larger and are difficult to be released through the pores of the silicone rubber, and thus an effective therapeutic effect cannot be obtained.

Comparative example 2

The difference from example 1 is only that the particle size of the drug was 15000 mesh, and the rest of the composition and the preparation method are the same as example 1.

The sample is dissolved in PBS solution at 37 ℃ by a drug dissolution tester, and the amount of the dissolved drug is tested by HPLC, so that the maximum drug dissolution amount in the first 3 days is 268 mug/d within 30 days, the maximum drug dissolution amount in the later days gradually becomes smooth and slow, and the average release rate in 30 days is 156 mug/d.

In the same manner as in example 1, before implantation into the airway, the airway was scratched by surgery to cause a wound surface, and bandaged with suture. After 30 days, the MSCT observes the degree of stenosis, and then the results show that: the average stenosis rate of the airway before the implantation of the airway stent is 71.0 percent, and the average stenosis rate after the implantation for 30 days is 60.8 percent, which shows that the airway stent has obvious effect after the implantation.

As can be seen from the comparison between example 1 and comparative example 2, when the mesh number of the drug is too high, the drug particles are smaller, the drug particles are easier to release through pores, the excessive release can cause the blood concentration to be too high, and researches report that the blood concentration of mometasone furoate is too high, and other side effects are easy to cause.

Comparative example 3

The only difference from example 1 is that the thickness of the silicone rubber stent is 0.3mm, and the rest of the composition and the preparation method are the same as those of example 1.

In the same manner as in example 1, before implantation into the airway, the airway was scratched by surgery to cause a wound surface, and bandaged with suture. After 30 days, the MSCT observes the degree of stenosis, and the process has different degrees of shift around 7-15 days.

As can be seen from the comparison between example 1 and comparative example 3, when the wall thickness of the tube body is low, the hardness of the product is too low, the supporting force is insufficient, and poor adhesion or slipping and displacement are likely to occur, and thus a good effect cannot be obtained.

Comparative example 4

The difference from example 6 is only that the thickness of the silicone rubber stent is 3mm, and the rest of the composition and the preparation method are the same as those of example 6.

Implanted in the same manner as in example 6, the stent could not be implanted into the airway.

It can be seen from a comparison of example 6 and comparative example 4 that when the wall thickness of the tube body is too thick, the product is not easily or not allowed to stand.

Comparative example 5

The difference from example 1 is only that the cross-linking density of the silicone rubber drug film was 2000g/mol, and the remaining composition and preparation method were the same as example 1.

The drug dissolution tester is used for dissolving the drug in a simulated solution at 37 ℃ and testing the amount of the dissolved drug by HPLC, so that the maximum drug dissolution amount in the first 3 days is 172 mug/d within 30 days, the maximum drug dissolution amount in the later days gradually becomes stable and slow, and the average release rate in the 30 days is 109 mug/d.

As can be seen from the comparison between example 1 and comparative example 5, when the cross-linking density of the silicone rubber stent is too low, the drug release rate of the product is too high, and other side effects are easily caused.

Comparative example 6

The only difference from example 1 was that the cross-linking density of the silicone rubber film was 10000g/mol, and the remaining composition and preparation method were the same as example 1.

The sample is dissolved in a simulated solution at 37 ℃ by a drug dissolution tester, and the amount of the dissolved drug is tested by HPLC, so that the maximum amount of the drug dissolved in the first 3 days is 41 mug/d within 30 days, the maximum amount gradually becomes stable and slow, and the average release degree within 30 days is 4.7 mug/d.

It is understood from comparison between example 1 and comparative example 6 that, when the cross-linking density of the silicone rubber is too high, the drug is hardly released and the therapeutic effect cannot be achieved.

The applicant declares that the above description is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be understood by those skilled in the art that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are within the scope and disclosure of the present invention.

Claims

1. An airway stent is characterized by comprising a silicon rubber matrix and a medicament, wherein the medicament is dispersed in the silicon rubber matrix, the silicon rubber matrix comprises a silicon rubber stent, the silicon rubber stent is in a tubular structure, and the thickness of the tubular structure is 0.5-2.0 mm;

the silicon rubber substrate also comprises a silicon rubber film, the silicon rubber film is arranged on the surface of the silicon rubber support, and the medicine is dispersed in the silicon rubber support and the silicon rubber film, or the silicon rubber film is arranged on the surface of the silicon rubber support, and the medicine is dispersed in the silicon rubber film;

the particle size of the dispersed medicine in the silicon rubber film is 500-10000 meshes, and the particle size of the dispersed medicine in the silicon rubber support is 1000-8000 meshes;

the cross-linking density of the silicon rubber film is 3000-8000g/mol, and the cross-linking density of the silicon rubber support is 3000-8000 g/mol.

2. The airway stent according to claim 1, wherein the silicone rubber stent and the silicone rubber membrane are bonded together by glue.

3. The airway stent according to claim 1, wherein the silicone rubber stent and the silicone rubber membrane are cured together in a semi-solid state.

4. The airway stent as claimed in claim 1, wherein the particle size of the dispersed drug in the silicone rubber membrane is 1000-8000 mesh.

5. The airway stent of claim 1, wherein the drug in the airway stent is released in an amount of 5-150 μ g per day.

6. The airway stent according to claim 1, wherein the silicone rubber stent has a hardness of 40-90A.

7. An airway stent as claimed in claim 1 wherein the silicone rubber membrane is 0.05-1mm thick.

8. An airway stent as claimed in claim 1 wherein the silicone rubber membrane is 0.1-0.5mm thick.

9. The airway stent according to claim 1, wherein the silicone rubber film has a hardness of 30 to 60A.

10. The airway stent of claim 1, wherein the drug comprises any one or a combination of at least two of aspirin, salicylic acid, sodium salicylate, magnesium salicylate, diflunisal, salsalate, ibuprofen, indomethacin, flurbiprofen, phenoxyibuprofen, naproxen, piroxicam, phenylbutazone, fenbufen, carprofen, ketoprofen, diclofenac, ketorolac, tetrafluorofenamic acid, sulindac, tolmetin, celecoxib, aminoglycoside antibiotics, anti-adhesion anti-scarring agents, macrolide antibiotics, cyclosporine a, berberine hydrochloride, paclitaxel, docetaxel, vinorelbine, elemene, or enalapril.

11. The airway stent of claim 10, wherein the aminoglycoside antibiotic comprises any one or a combination of at least two of streptomycin, gentamicin, kanamycin, sisomicin, tobramycin, amikacin, netilmicin, nebivoxim, isepamicin, lividomycin, micronomicin, paromomycin, neomycin, or aspartame.

12. An airway stent as claimed in claim 10, wherein said anti-adhesion anti-scarring agent comprises a glucocorticoid: triamcinolone acetonide, dexamethasone, betamethasone, cortisone, hydrocortisone, mometasone furoate, rimexolone, prednisone, prednisolone, methylprednisolone, triamcinolone, budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide, fluocinolone, clobetasol, halometasone, difloron diacetate, halomethasone or fluocinolone acetonide, or a combination of at least two thereof.

13. The airway stent of claim 10, wherein the macrolide antibiotics include any one or a combination of at least two of erythromycin and derivatives thereof, azithromycin, midecamycin and derivatives thereof, spiramycin and derivatives thereof, acetylspiramycin, tacrolimus, sirolimus, everolimus, amphotericin B, pentamycin, fidaxomicin, telithromycin, or mitomycin.

14. The airway stent of claim 1, wherein the drug comprises any one of rapamycin, mometasone furoate, mitomycin, or dexamethasone, or a combination of at least two thereof.

15. The airway stent according to claim 1, wherein the cross-linking density of the silicone rubber membrane is 4000-6000 g/mol.

16. The airway stent according to claim 1, wherein the cross-linking density of the silicone rubber stent is 5000-8000 g/mol.

17. The airway stent according to claim 1, wherein the silicone rubber film comprises 60-90% of silicone rubber, 4-39.8% of drug, 0.1-3% of cross-linking agent and 0.1-3% of catalyst by mass percentage.

18. The airway stent of claim 17, wherein the silicone rubber comprises any one of, or a combination of at least two of, heat-vulcanized silicone rubber, dow corning Silastic-382 medical grade silicone rubber, dow corning Q7 medical grade silicone rubber series, dow corning C6 medical grade silicone rubber series, or implant grade MDX series.

19. An airway stent as claimed in claim 17 wherein the cross-linking agent comprises hydrogen-containing silicone oil and/or hydrogen-containing silicone.

20. The airway stent of claim 17, wherein the catalyst comprises any one of a platinum complex, a ruthenium complex, or a rhodium complex, or a combination of at least two thereof.

21. The airway stent according to claim 1, wherein the preparation method of the silicone rubber film comprises the following steps: and mixing the silicon rubber, the medicine, the cross-linking agent and the catalyst, and carrying out vulcanization crosslinking to obtain the silicon rubber film.

22. The airway stent according to claim 1, wherein the silicone rubber stent comprises 60-99.8% of silicone rubber, 0-39.8% of drug, 0.1-3% of cross-linking agent and 0.1-3% of catalyst in percentage by mass.

23. The airway stent of claim 22, wherein the silicone rubber for the silicone rubber stent comprises any one of or a combination of at least two of heat-vulcanized silicone rubber, room temperature vulcanized silicone rubber, low temperature vulcanized silicone rubber, Dow Corning Silastic-382 medical grade silicone rubber, Dow Corning Q7 medical grade silicone rubber series, or implant grade MDX series.

24. An airway stent as claimed in claim 22 wherein the cross-linking agent comprises hydrogen-containing silicone oil and/or hydrogen-containing silicone.

25. The airway stent of claim 22, wherein the catalyst comprises any one of a platinum complex, a ruthenium complex, or a rhodium complex, or a combination of at least two thereof.

26. The airway stent according to claim 22, wherein the preparation method of the silicone rubber stent comprises the following steps: and mixing the silicon rubber, a cross-linking agent and a catalyst, and carrying out vulcanization crosslinking to obtain the silicon rubber support.

27. The airway stent of claim 1, wherein the period of drug release in the airway stent is 15 days to 12 months.

28. The airway stent of claim 1, wherein the period of drug release from the airway stent is 1-3 months.

29. Use of an airway stent according to any of claims 1 to 28 in a drug delivery system.