阅读说明：本技术 一种气道支架及其应用 (Airway stent and application thereof ) 是由 夏佩佩 邢若豪 晏伟 魏征 于 2019-12-31 设计创作，主要内容包括：本发明提供了一种气道支架及其应用,所述气道支架包括硅橡胶基体和药物,所述药物分散在硅橡胶基体的内部；所述气道支架植入气道中,能够控制药物的释放情况,气道支架中含有药物能够对气道损伤具有较好的治疗效果,并能用于扩张狭窄气道和抑制气道再狭窄的功效。(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.)

1. An airway stent is characterized by comprising a silicon rubber matrix and a drug, wherein the drug is dispersed in the silicon rubber matrix.

2. The airway bracket of claim 1, wherein the silicone rubber base comprises a silicone rubber bracket;

preferably, the drug is dispersed inside the silicone rubber stent;

preferably, the silicone rubber substrate further comprises a silicone rubber film, the silicone rubber film is arranged on the surface of the silicone rubber stent, and the medicine is dispersed in the silicone rubber film;

preferably, the silicone rubber substrate further comprises a silicone rubber film, the silicone rubber film is arranged on the surface of the silicone rubber stent, and the medicine is dispersed in the silicone rubber stent and the silicone rubber film;

preferably, the silicone rubber support and the silicone rubber film are bonded together by glue;

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

3. The airway stent as claimed in claim 1 or 2, wherein the particle size of the dispersed drug in the silicone rubber membrane is 500-10000 meshes, preferably 1000-8000 meshes;

preferably, the particle size of the dispersed drug in the silicone rubber stent is 1000-8000 meshes;

preferably, the drug in the airway stent releases 5-150 mug of drug per day.

4. An airway stent according to any of claims 1 to 3, characterized in that the silicone rubber stent is in the shape of a tubular structure;

preferably, the thickness of the tubular structure is 0.5-2.0 mm;

preferably, the hardness of the silicon rubber support is 40-90A;

preferably, the thickness of the silicone rubber film is 0.05-1mm, preferably 0.1-0.5 mm;

preferably, the silicone rubber film has a hardness of 30 to 60A.

5. An airway stent as claimed in any one of claims 1 to 4 wherein the drug includes any one 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 or a combination of at least two thereof;

preferably, the aminoglycoside antibiotic comprises 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;

preferably, the anti-adhesion and 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;

preferably, the macrolide antibiotics comprise 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;

preferably, the drug comprises any one of rapamycin, mometasone furoate, mitomycin or dexamethasone or a combination of at least two thereof.

6. An airway stent according to any of claims 1-5 characterized in that the cross-linking density of the silicone rubber membrane is 3000-8000g/mol, preferably 4000-6000 g/mol;

preferably, the cross-linking density of the silicone rubber stent is 3000-8000g/mol, preferably 5000-8000 g/mol.

7. The airway stent according to any one of claims 1 to 6, wherein the silicon rubber film comprises 60 to 90 mass percent of silicon rubber, 4 to 39.8 mass percent of drug, 0.1 to 3 mass percent of cross-linking agent and 0.1 to 3 mass percent of catalyst;

preferably, 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;

preferably, the cross-linking agent comprises hydrogen-containing silicone oil and/or hydrogen-containing siloxane;

preferably, the catalyst comprises any one of a platinum complex, a ruthenium complex, or a rhodium complex, or a combination of at least two thereof;

preferably, 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.

8. An airway stent according to any one of claims 1 to 7, characterized in that the silicone rubber stent comprises 60 to 99.8 percent of silicone rubber, 0 to 39.8 percent of drug, 0.1 to 3 percent of cross-linking agent and 0.1 to 3 percent of catalyst by mass percentage;

preferably, the silicone rubber used for the silicone rubber bracket comprises any one or a combination of at least two of hot 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;

preferably, the cross-linking agent comprises hydrogen-containing silicone oil and/or hydrogen-containing siloxane;

preferably, the catalyst comprises any one of a platinum complex, a ruthenium complex, or a rhodium complex, or a combination of at least two thereof;

preferably, 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.

9. An airway stent according to any of claims 1 to 8 wherein the period of release of drug from the airway stent is from 15 days to 12 months;

preferably, the release period of the drug in the airway stent is 1-3 months.

10. Use of an airway stent according to any of claims 1 to 9 in a drug delivery system.

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 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 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.