CN111714260A

CN111714260A - Support and application thereof

Info

Publication number: CN111714260A
Application number: CN202010694668.6A
Authority: CN
Inventors: 夏佩佩; 晏伟; 魏征
Original assignee: Shanghai Pu Ruitong Medical Technology Co ltd
Current assignee: Shanghai Pu Ruitong Medical Technology Co ltd
Priority date: 2020-07-17
Filing date: 2020-07-17
Publication date: 2020-09-29
Anticipated expiration: 2040-07-17
Also published as: CN111714260B

Abstract

The invention provides a bracket and application thereof, wherein the bracket is used for a urinary system pipeline and comprises a bracket base body and a medicament arranged on the bracket base body; when the stent is implanted into the urinary system pipeline, the stent matrix plays a role in supporting and draining the urinary system pipeline, the medicine is used for preventing or reducing the occurrence of the urinary system pipeline restenosis, and the stent has the treatment effect of low dosage and high efficiency, and has a long medicine release period and good slow release capability. In addition, the stent of the invention can achieve the target effect, effectively avoids the situation that the liver needs to metabolize firstly when the medicine is taken orally, the dosage is about 10 percent of the dosage of the oral medicine or the injection mode, and the side effect of the medicine to the whole body is greatly reduced.

Description

Support and application thereof

Technical Field

The invention belongs to the field of medical instruments, and relates to a bracket and application thereof.

Background

Urinary system canal stenosis (e.g. ureteral stenosis, urethral stricture) is a common disease of the urinary system, besides congenital stenosis, inflammation and injury are main causes of urinary system canal stenosis, for example, the common causes include ureteroscopy, holmium and thulium laser lithotripsy, various pelvic surgeries, ureteral infection, urethral lumen infection and the like.

At present, the clinical treatment modes for the urinary system canal stenosis include repeated dilatation, incision, anastomosis, dragging, alternative forming and other operation modes, and after the operation, a patient needs to implant a stent for supporting and drainage. At present, the stent on the market only has the functions of physical support and drainage and does not play a role in repairing or treating the injury, and the stent implanted can stimulate the body to cause inflammation instead, so that scar tissues are formed at the injured part, and the restenosis of the urinary system pipeline is caused. For the urinary system canal restenosis, if repeated operations are performed, other complications are easily caused, which not only brings great pains to the body and spirit of the patient, but also increases the economic burden.

Therefore, it is desirable to provide a stent that can prevent or reduce restenosis in the urinary tract.

Disclosure of Invention

The invention aims to provide a stent and application thereof, the stent can play a role in supporting and draining a urinary system pipeline on one hand, and can prevent or reduce the occurrence of urinary system pipeline restenosis on the other hand, and the stent has a low-dose and high-efficiency treatment effect, a long drug release period and a good slow release capacity.

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

one of the objectives of the present invention is to provide a stent for urinary tract, which comprises a stent base and a drug disposed on the stent base. When the stent is implanted into a urinary system pipeline, the stent matrix plays a role in supporting and draining the urinary system pipeline, and the medicine is used for preventing or reducing the occurrence of restenosis of the urinary system pipeline.

In one embodiment, the urinary system conduit is a ureter and/or a urethra, and correspondingly, the stent is a ureteral stent and/or a urethral stent. Specifically, the stent implanted into the urinary system conduit may be a ureteral stent, a urethral stent, or a combination of a ureteral stent and a urethral stent, and those skilled in the art may adjust the stent according to actual needs. The ureter stent is placed in a ureter, so that the ureter stent can play a role in supporting and draining the ureter on one hand, and can prevent or reduce the occurrence of ureter restenosis on the other hand; the urethral stent is arranged in the urethra, on one hand, the urethral stent can play a role in supporting and draining the urethra, and on the other hand, the urethral stent can prevent or reduce the occurrence of urethral restenosis.

In one embodiment, one or more ureteral stents are implanted in the ureter, and the specific implantation number can be adjusted by one skilled in the art according to actual needs; similarly, one or more than one urethral stent can be implanted in the urethra, and the specific number of the implanted urethral stents can be adjusted by the skilled person according to the actual needs.

In one specific embodiment, the ureteral stent may be a single J-tube, a double J-tube, or a straight tube, and one skilled in the art may select the ureteral stent according to actual needs.

In one embodiment, the urethral support can be a single-cavity catheter, a double-cavity catheter or a three-cavity catheter; the urethral stent can be saccular or not; the selection and adjustment can be carried out by the person skilled in the art according to the actual needs.

In one embodiment, the amount of drug carried by a single stent is from 30 μ g to 200mg, such as 30 μ g, 50 μ g, 100 μ g, 500 μ g, 800 μ g, 1mg, 10mg, 50mg, 100mg, 150mg, 200mg, and the like.

In one embodiment, a single stent releases a drug amount of 5 μ g to 2mg per day, e.g., 5 μ g, 10 μ g, 50 μ g, 100 μ g, 300 μ g, 500 μ g, 800 μ g, 1mg, 1.2mg, 1.5mg, 1.8mg, 2mg, etc.

In one embodiment, the release period of the drug from a single stent is 5 to 90 days, such as 5 days, 10 days, 20 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, etc.

The single stent can be a single ureteral stent or a single urethral stent.

The single bracket releases 5 mu g-2mg of medicine every day, and the total medicine carrying amount of the single bracket is in the range of 30 mu g-200mg so as to enable the medicine amount released every day and the total medicine amount to reach the threshold value of action, thereby being capable of carrying out effective treatment. In addition, the single stent releases 5 mu g-2mg of drug per day for 5-90 days, and the release speed is stable and the release is uniform.

In one embodiment, the drug of a single stent is not released or is released in an amount of less than 1mg (e.g., 5 μ g, 10 μ g, 50 μ g, 100 μ g, 300 μ g, 500 μ g, 800 μ g, 1mg, etc.) from 1h to 7 days (e.g., 1h, 6h, 12h, 18h, 1 day, 2 days, 3 days, 4 days, 45 days, 6 days, 7 days, etc.) after the stent has been implanted.

The drug of a single stent is not released or the release amount is less than 1mg within 1h-7 days after the stent is implanted, so that the functions of defense and repair of the body are reduced to avoid the effect of a large amount of drug at the early stage, thereby causing infection diffusion and delaying wound healing.

In one embodiment, the medicament comprises a medicament comprising a glucocorticoid. In the early stage of inflammation, glucocorticoid can stabilize the endolysosomal membrane, protect mitochondria, and relieve exudation, edema, telangiectasia, leukocyte infiltration and phagocytosis reaction, thereby improving symptoms such as red, swelling, heat and pain; in the later stage of inflammation, glucocorticoid can inhibit the proliferation of capillary and fibroblasts, and inhibit the synthesis of collagen and mucopolysaccharide and the proliferation of granulation tissue, thereby preventing adhesion and scar formation, and further preventing or reducing the occurrence of urinary system canal restenosis.

It is noted that glucocorticoids do not contribute to wound healing, and as mentioned above, the drug of a single stent is not released or is released in an amount of less than 1mg 1h-7 days after implantation of the stent, so that there is sufficient time for the drug containing glucocorticoids to be released after wound healing.

In one embodiment, the glucocorticoid-containing drug comprises any one or a combination of at least two of clobetasol, amcinonide, triamcinolone acetonide, tranilast, budesonide, mometasone furoate, dexamethasone, betamethasone, flumethasone, fluorometholone, hydrocortisone base, rimexolone, desoximetasone, cotolone, prednisolone, triamcinolone, rofleponide, ciclesonide, prednisone, cortisone, or triamcinolone.

In one embodiment, the medicament further comprises an anti-infective medicament comprising any one or a combination of at least two of beta lactams, macrolides, quinolones, aminoglycosides, antivirals or antifungals, taking into account that urinary system infection is a common complication after stent implantation.

In one embodiment, the scaffold matrix is made of degradable material and/or non-degradable material.

In one embodiment, the scaffold matrix is made of a degradable material.

In one embodiment, the degradable material comprises any one or a combination of at least two of polylactide, polylactide-glycolide, polyglycolide, polyglycolic acid/polylactic acid copolymer, polyethylene glycol, polycaprolactone, polyorthoester, polyglycolic acid, polybutylene succinate, caprolactone-lactide copolymer, or polyhydroxyalkanoate.

In one embodiment, the scaffold substrate is made of a non-degradable material.

In one embodiment, the non-degradable material comprises any one of rubber, silicone rubber, polyester, polyvinyl chloride, polyurethane, or a metal (e.g., nitinol) or a combination of at least two thereof.

In one embodiment, the scaffold matrix has a hardness of 60-99A, such as 60A, 65A, 70A, 75A, 80A, 85A, 90A, 95A, 99A, and the like; the support matrix of this hardness can guarantee to have better supporting role to the urinary system pipeline, if the hardness of support matrix is too low, then be easily by the extrusion deformation, be difficult to play supporting role to the urinary system pipeline to influence treatment, if the hardness of support matrix is too high, then difficult transport, and probably damage the urinary system pipeline.

According to one aspect of the invention, the drug is dispersed within the interior of the stent matrix to form a matrix-type stent.

In one embodiment, the drug may be dispersed throughout the interior of the stent matrix to provide a therapeutic effect as a whole; the drug can also be dispersed inside a specific position of the stent matrix so as to carry out targeted local treatment according to the injury condition.

In one embodiment, the drug may be uniformly dispersed throughout the interior of the stent matrix to provide a therapeutic effect as a whole; the drug can also be non-uniformly dispersed in the whole stent matrix, more parts with serious damage can be dispersed, and less parts with lighter damage can be dispersed.

In one embodiment, the particle size of the drug is 800-12500 mesh, such as 800 mesh, 1000 mesh, 2000 mesh, 3000 mesh, 4000 mesh, 5000 mesh, 6000 mesh, 7000 mesh, 8000 mesh, 9000 mesh, 10000 mesh, 12500 mesh; the release rate of the medicine is controlled by controlling the mesh number of the medicine, so that the medicine effect and the release period are controlled; when the mesh number of the drug is too low, the particle size of the drug is large, and the drug is difficult to dissolve out from the inside of the stent matrix, so that the treatment effect is influenced; when the mesh number of the drug is too high, the particle size of the drug is small and the drug is easily dissolved out from the inside of the stent, resulting in too high blood concentration, which may cause other side reactions.

In one embodiment, when the material of the stent matrix is silicone rubber, the stent includes 45-90% (e.g., 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, etc.) of silicone rubber, 5-50% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, etc.) of drug, 0.1-3% (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.) of cross-linking agent, and 0.1-3% (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.) of catalyst by mass; the additive amount of each substance in the stent is controlled, so that the substances are mutually matched and act, and the release rate of the drug is controlled, thereby controlling the drug effect and the release period.

In one embodiment, the cross-linking agent comprises hydrogen-containing silicone oil and/or hydrogen-containing silicone.

In one embodiment, the catalyst comprises any one of platinum, a platinum complex, a ruthenium complex, or a rhodium complex, or a combination of at least two thereof.

In one embodiment, the silicone rubber has a crosslink density of 1000-8000g/mol, such as 1500g/mol, 2000g/mol, 2500g/mol, 3000g/mol, 3500g/mol, 4000g/mol, 4500g/mol, 5000g/mol, 5500g/mol, 6000g/mol, 6500g/mol, 7000g/mol, 7500g/mol, or 8000g/mol, and the like.

The crosslinking density of the silicone rubber refers to the number of effective network chains contained in the unit volume of the silicone rubber, and can represent the crosslinking degree of the silicone rubber. During the test, it was found that the greater the crosslink density of the silicone rubber, the smaller the drug release amount under the same conditions. When the medicine is dispersed in the silicon rubber, the cross-linking density of the silicon rubber is controlled, so that the release rate of the medicine is controlled, and a better treatment effect is achieved. However, the crosslinking density of silicone rubber affects the properties of the silicone rubber, such as elastic modulus, breaking strength, elongation at break, and the like. According to the test, the cross-linking density of the silicone rubber has the best elasticity and slow release effect within the range.

In one embodiment, the method for preparing the stent comprises the following steps: and mixing the silicon rubber, the medicine, the cross-linking agent and the catalyst, and carrying out vulcanization and cross-linking to obtain the stent.

In one embodiment, when the material of the stent matrix is a degradable material, the stent includes 49-95% (e.g., 49%, 52%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, etc.) of the degradable material, 4-50% (e.g., 4%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, etc.) of the drug, and optionally 1-20% (e.g., 1%, 3%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, etc.) of the water-soluble polymer by mass.

With the urine flowing out, the degradable material is degraded by the action of the optional water-soluble polymer, namely, the stent matrix is degraded by the action of the optional water-soluble polymer. As the stent matrix degrades, the drug dispersed within the stent matrix is released. The degradation rate of the stent matrix can be controlled by controlling the addition of the optional water-soluble polymer and the outflow of urine, so that the slow release of the drug can be controlled, and better slow release and treatment effects can be achieved. Experiments show that when 1-20% of water-soluble polymer is added, the drug release rate is better.

In one embodiment, the water-soluble polymer includes any one or a combination of at least two of chitosan, gelatin, gum arabic, hyaluronic acid, cellulose and its derivatives, polyacrylamide, polyacrylic acid, polyvinylpyrrolidone, polyvinyl acid, polymaleic anhydride, polyquaternium, or starch.

In one embodiment, the method for preparing the stent comprises the following steps: mixing degradable materials, the medicine and optional water-soluble polymers under a melting condition, and performing extrusion molding to obtain the stent. The method needs to match the melting points of the degradable material and the drug so as to prevent the drug from being inactivated due to too high temperature.

In one embodiment, the method for preparing the stent comprises the following steps: mixing degradable materials, medicines and optional water-soluble polymers in a solvent, removing the solvent, and heating and shaping to obtain the stent.

In the matrix type stent, since the drug is dispersed in the interior of the stent matrix, when selecting the material for the stent matrix, it is necessary to select a material capable of releasing the drug, and the material may be polyester in addition to the above-mentioned silicone rubber and degradable material. The matrix type stent has a relatively long drug release period and can be suitable for cases requiring long-term stent implantation.

According to another aspect of the present invention, the drug is dispersed on the outer surface of the stent substrate to form a drug coating on the outer surface of the stent substrate, and the stent is a coating-type stent.

In one embodiment, the drug coating and the stent matrix are connected together by crosslinking, wherein the crosslinking includes chemical crosslinking including polycondensation crosslinking or polyaddition crosslinking, and physical crosslinking including any one of photo-crosslinking, thermal crosslinking, radiation crosslinking, or natural crosslinking.

In one embodiment, the drug coating is disposed on the outer surface of the stent matrix in a coated or wrapped manner.

In one embodiment, the coating comprises any one of dipping, spinning, spraying or brushing, preferably spraying.

In one embodiment, the drug coating layer may be disposed on the entire outer surface of the stent matrix, or may be partially disposed on the outer surface of the stent matrix, and may be adjusted by those skilled in the art according to actual needs.

In one embodiment, the drug coating has a thickness of 0.01 to 1mm, such as 0.01mm, 0.05mm, 0.1mm, 0.3mm, 0.5mm, 0.7mm, or 1mm, and the like.

In one embodiment, the holder base includes opposite ends, one of which is an inlet end for introducing urine and the other of which is an outlet end for discharging urine. The thickness of the drug coating of the leading-in end is larger than that of the drug coating of the leading-out end.

In one embodiment, the introduction end of the ureteral stent is a kidney-proximal end, and the extraction end of the ureteral stent is a bladder-proximal end.

In one embodiment, the introduction end of the urethral stent is a proximal bladder end, and the exit end of the urethral stent is a proximal urethral orifice end.

Considering that in the urinary system, 1-2L of urine is normally generated every day, the urine flows out from top to bottom along the ureter and the urethra, the thickness of the drug coating at the leading-in end is larger than that of the drug coating at the leading-out end, and the drug concentration difference caused by urine scouring can be compensated. The thickness of the medicine coating can be changed in a linear type, a curve type or a gradient type from the leading-in end to the leading-out end.

In one embodiment, the method for preparing the stent comprises the following steps: adding (dissolving) a biodegradable polymer material with a mass percentage of 40-98% (e.g. 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, etc.) and a drug with a mass percentage of 2-60% (e.g. 2%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, etc.) into a solvent, uniformly mixing to obtain a mixed solution, coating the mixed solution on the outer surface of a stent matrix, and volatilizing the solvent to form a drug coating, thereby obtaining the stent. When in use, the medicine can be released along with the degradation of the biodegradable high polymer material. The stent matrix can be prepared in advance by methods such as extrusion molding and weaving molding, and the material of the stent matrix is not limited as long as the stent matrix can be combined with a biodegradable high polymer material serving as a drug-carrying substrate.

In one embodiment, the biodegradable polymer material is any one or a combination of at least two of gelatin, starch, hyaluronic acid, cellulose, chitosan, polylactic acid, polyglycolic acid, polycaprolactone, polylactide-caprolactone, or polylactic acid-caprolactone.

In one embodiment, the solvent may be any one of water, dichloromethane, chloroform, acetone, isopropanol, ethanol, tetrahydrofuran, hexafluoroisopropanol, hexafluoroacetone, dimethyl sulfoxide, acetonitrile, diethyl ether, ethyl acetate, n-hexane, pyridine, toluene, benzene, dimethylformamide, n-heptane, methanol, ethylamine, lactic acid, petroleum ether, glycerol, octanoic acid, n-hexanol, or cyclohexane, or a combination of at least two thereof.

In one embodiment, the mixed liquid is atomized into particles by using an atomization device and then coated on the outer surface of the stent matrix.

In one embodiment, the particles are coated on the outer surface of the stent matrix in a wet or semi-dry state.

In one embodiment, the particle size of the microparticles is 50nm to 500 μm (e.g., 50nm, 100nm, 300nm, 500nm, 800nm, 1 μm, 5 μm, 10 μm, 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500 μm, etc.), preferably 500nm to 200 μm.

In one embodiment, the method for preparing the stent further comprises pre-treating the outer surface of the stent substrate before the coating.

In one embodiment, the treatment comprises any one of plasma treatment, swelling treatment, sand blasting, sanding treatment, dermatoglyph treatment, electrostatic treatment, or wetting treatment, or a combination of at least two thereof.

In one specific embodiment, the mixed solution further includes a polymer with a long degradation period or that is not degradable, the mass percentage of the polymer with a long degradation period or that is not degradable is 0.5% to 10% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, etc.), at this time, the mass percentage of the biodegradable polymer material is 40% to 95%, and the mass percentage of the drug is 2% to 50%. In this way, the release rate of the drug can be reduced.

In one embodiment, the polymer with a long degradation period is any one of or a combination of at least two of polylactic acid, polyglycolic acid, a blend containing polyglycolic acid, a polyglycolic acid copolymer, or polyvinyl alcohol.

In one embodiment, the non-degradable polymer is any one of polyvinylpyrrolidone, parylene, silicone oil, silicone gel, silicone rubber, or polyethylene glycol, or a combination of at least two thereof.

In one embodiment, the method for preparing the stent comprises the following steps: the stent is prepared by uniformly mixing 24-80% (e.g., 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, etc.) of silicone rubber, 18-70% (e.g., 20%, 30%, 40%, 50%, 60%, 70%, etc.) of micronized drug, 0.1-3% (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.) of crosslinking agent, and 0.1-3% (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.) of catalyst in percentage by mass to obtain a mixture, and then combining the mixture and the stent matrix by curing. The stent base may be prepared in advance by extrusion molding, braiding molding, or the like.

In one embodiment, the method for preparing the stent comprises the following steps: uniformly mixing 24-80% of silicon rubber, 18-70% of micronized medicine, 0.1-3% of cross-linking agent and 0.1-3% of catalyst by mass percentage to obtain a mixture, curing the mixture to obtain a medicine film (namely a medicine coating positioned on the outer surface of a stent matrix after the stent is prepared), and then combining the medicine film and the stent matrix together in a secondary curing or gluing mode to obtain the stent. The material of the support substrate is not limited, and the support substrate can be bonded with the silicon rubber medical membrane in an adhesive or secondary curing manner. The stent base may be prepared in advance by extrusion molding, braiding molding, or the like.

The secondary curing is suitable for a support matrix made of silicon rubber, and the incompletely cured medicine film and the support matrix are subjected to secondary vulcanization through pressurization and/or heating, so that the support matrix and the medicine film are completely combined. The method does not need to add new materials, and the two materials are combined more firmly and have stable performance.

The adhesive is suitable for the support matrix made of all materials, the selected adhesive can be any one or the combination of at least two of silicon rubber, UV (ultraviolet) adhesive, resin adhesive, hot melt adhesive, pressure-sensitive adhesive, latex and the like, and the preferred is silicon rubber.

The thickness of the drug film affects the concentration gradient of the drug, and the drug films with different thicknesses can cause the drug to exude to different degrees in the release process, so that the release rates are different. When the thickness of the film is 0.01-1mm, the medicine has better effect and longer release period.

In both embodiments, the cross-linking agent comprises a hydrogen-containing silicone oil and/or a hydrogen-containing silicone.

In both embodiments, the catalyst comprises any one or a combination of at least two of platinum, a platinum complex, a ruthenium complex, or a rhodium complex.

In the above two embodiments, the particle size of the micronized drug is 800-; the release rate of the medicine is controlled by controlling the mesh number of the medicine, thereby controlling the efficacy and the release period. The relationship between the mesh number of the drug and the release rate of the drug is as described above and will not be described herein.

In both embodiments, the silicone rubber has a crosslinking density of 1000-8000g/mol, for example 1500g/mol, 2000g/mol, 2500g/mol, 3000g/mol, 3500g/mol, 4000g/mol, 4500g/mol, 5000g/mol, 5500g/mol, 6000g/mol, 6500g/mol, 7000g/mol, 7500g/mol or 8000g/mol, etc. The release rate of the drug is controlled by controlling the crosslinking density of the silicon rubber in the drug coating, thereby controlling the drug effect and the release period. The relationship between the cross-linking density of the silicone rubber and the release rate of the drug is as described above and will not be described herein.

On the basis of any one of the two aspects, a controlled release layer and/or a hydrophilic coating layer is further arranged on the outer surface of the stent matrix or the outer surface of the drug coating layer.

The controlled release layer can control the release rate of the drug, thereby controlling the drug effect and the release period.

The bracket can generate certain friction with the tube wall of the urinary system tube in the process of implanting the bracket into the urinary system tube, thereby causing a patient to feel painful to a certain degree. In order to reduce the friction force in the implantation process, a hydrophilic coating can be arranged on the outer surface of the stent base body or the outer surface of the drug coating, when the hydrophilic coating is in contact with water or water-containing tissues, water drops form a small contact angle on the surface of the hydrophilic coating, so that the water drops have a large spreading area, a super-lubricating surface water film is formed, and the friction force in the process of implanting the stent into the urinary system pipeline is reduced.

In one embodiment, the thickness of the controlled release layer is 0.01 to 1mm, such as 0.01mm, 0.05mm, 0.1mm, 0.2mm, 0.3mm, 0.4mm, 0.5mm, 0.6mm, 0.7mm, 0.8mm, 0.9mm, 1mm, and the like.

In one embodiment, the material of the controlled release layer is silicone rubber.

In one embodiment, the silicone rubber has a crosslink density of 1000-8000g/mol, such as 1000g/mol, 1500g/mol, 2000g/mol, 2500g/mol, 3000g/mol, 3500g/mol, 4000g/mol, 4500g/mol, 5000g/mol, 5500g/mol, 6000g/mol, 8000g/mol, and the like.

In one embodiment, the silicone rubber and the stent matrix or drug coating are bonded together by glue.

In one embodiment, the silicone rubber and the stent matrix or drug coating are cured together in a semi-solid state.

When the controlled release layer is made of silicon rubber, the release rate of the drug is controlled by controlling the crosslinking density of the controlled release layer, so that the drug effect and the release period are controlled. The relationship between the cross-linking density of the silicone rubber and the release rate of the drug is as described above and will not be described herein.

In one embodiment, the hydrophilic coating has a thickness of 0.01 to 0.5mm, such as 0.01mm, 0.12mm, 0.15mm, 0.17mm, 0.2mm, 0.22mm, 0.25mm, 0.27mm, 0.3mm, 0.5mm, and the like.

In one embodiment, the material of the hydrophilic coating is any one or a combination of at least two of polyethylene oxide, polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, polyisocyanate, sodium hyaluronate, and maleic acid. In this manner, the hydrophilic coating does not chemically react with the drug to modify or inactivate the drug.

In one embodiment, the thickness of the hydrophilic coating is 0.01-0.5mm, so that the hydrophilic coating can uniformly and sufficiently contact with water and rapidly spread to form an ultra-smooth surface water film on one hand, and the release rate of the drug can be further controlled through the arrangement of the hydrophilic coating on the other hand, thereby controlling the drug effect and the release period.

In one embodiment, the stent includes both a controlled release layer disposed on the outer surface of the stent substrate or on the outer surface of the drug coating and a hydrophilic coating disposed on the outer surface of the controlled release layer.

The drug coating and/or the controlled release layer and/or the hydrophilic coating are arranged, so that the diameter of the finally obtained stent is 0.1-1mm larger than that of the conventional stent in the market, the adherence of the stent can be increased, namely, the stent can be tightly combined with the tube wall of the urinary system pipeline, the tube wall has certain elasticity, and repeated experiments show that the implantation of the urethral stent cannot be influenced by the expansion within 1mm, and the additional discomfort caused by the expansion of the tube wall cannot be caused. The bracket is tightly combined with the tube wall of the urinary system pipeline, which is favorable for the drug to be absorbed by the mucosa layer of the tube wall.

In addition, for the coating type stent, the controlled release layer and/or the hydrophilic coating layer are/is arranged, so that the drug coating layer can be prevented from falling off due to friction during the implantation process.

It is a further object of the present invention to provide a use of the stent according to the first object for the preparation of a drug delivery system.

In one embodiment, the stent is used for supporting and draining the urinary tract and preventing or reducing the occurrence of restenosis of the urinary tract; further, for use in the ureter and/or urethra.

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

the stent is used for the urinary system pipeline and comprises a stent matrix and a medicament arranged on the stent matrix, when the stent is implanted into the urinary system pipeline, the stent matrix plays a role in supporting and draining the urinary system pipeline, the medicament is used for preventing or reducing the occurrence of the restenosis of the urinary system pipeline, and the stent has a low-dose and high-efficiency treatment effect, a long medicament release period and a good slow release capacity. In addition, the stent of the invention can achieve the target effect, effectively avoids the situation that the liver needs to metabolize firstly when the medicine is taken orally, the dosage is about 10 percent of the dosage of the oral medicine or the injection mode, and the side effect of the medicine to the whole body is greatly reduced.

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.

Example 1

The embodiment provides a stent, which comprises a stent matrix and a medicament containing glucocorticoid dispersed in the stent matrix, wherein the medicament containing glucocorticoid is mometasone furoate, the average particle size is 5000 meshes, the stent matrix is made of silicon rubber, and the cross-linking density of the silicon rubber is 5000 g/mol.

The embodiment provides a preparation method of a stent, which comprises the following steps: mixing 10 parts by weight of medicine (mometasone furoate) and 30 parts by weight of silicon rubber (HTV medical silicon rubber with the molecular weight of 20-100 ten thousand), 1.2 parts by weight of cross-linking agent (hydroxyl silicone oil) and 1.2 parts by weight of catalyst (platinum) on a rubber mixing mill until the mixture is uniform, vulcanizing and crosslinking, and extruding the mixture on an extruder to form the bracket.

The physical properties of the bracket of the embodiment are tested according to the test method of the standard GB/T531, and it can be known that: the hardness of the stent matrix is 80A.

The support force of the stent was tested using a radial support dynamometer with a 10% compression force value of 106N.

The content of the drug components in the sample is calculated according to the weight, the sample is subjected to drug dissolution in a simulated urine solution at 37 ℃ by using a drug dissolution tester, and the amount of the dissolved drug is tested by using High Performance Liquid Chromatography (HPLC), so that the maximum drug dissolution amount in the first 7 days is 200 mug/d, the total drug release amount in the first 7 days is 1055 mug, and the average release degree in the 30 days is 80 mug/d within 30 days.

The ureteral stent with the specification of 8F is prepared by the method, and animal experiments are carried out on the ureteral stent:

establishing ureter scar mechanism animal model, taking 10 female New Zealand rabbits (each rabbit has 2 ureters), establishing injury model in ureter with holmium laser, after debridement, measuring diameter D1 of narrow section and diameter D2 of normal ureter at far end of narrow section by radiography, and utilizing

Calculating the ureter stenosis degree.

Animals were divided into an experimental group and a control group, 5 of the experimental group were implanted into self-made ureteral stents (8F standard, with mometasone furoate, average released dose of 80 μ g per day within 30 days), and the control group was implanted into commercially available ureteral stents without drug of 8F standard. After 1 month, the tube is pulled out, the scar condition and the stenosis degree are measured and observed, and the observation result is shown in the table 1 after 1 month follow-up.

TABLE 1

As can be seen from Table 1, the experimental stent and the control stent are implanted randomly, the urethral stricture degree is measured by radiography, when the catheter is pulled out after one month of implantation, the stricture degree of the experimental group is 12.94 +/-2.02%, the stricture degree of the control group is 21.8 +/-11.8%, P is 0.043 < 0.05, and the significant difference exists; after the tube is pulled out for 1 month, the stenosis degree of the experimental group is 7.00 +/-4.57%, the stenosis degree of the control group is 22.1 +/-19.1%, and the P is 0.035 < 0.05, so that the significant difference is realized.

Dissecting after 1 month of tube drawing, taking tissue slices, analyzing by using Image-Pro Plus 6.0 software, selecting 8 sections of each slice, and measuring the damage depth of the tissue. The depth of the injury of the experimental group is 1554 +/-115 mu m, the depth of the injury of the control group is 1777 +/-139 mu m, the P is 0.001-0.05, and the obvious difference exists.

Tissue sections were taken, stained, and the area percentage of collagen fibers was measured using Image-pro plus 6.0 analysis software, with the area percentage of collagen fibers being 51.78 + -5.96% for the experimental group and 69.96 + -3.88% for the control group. P is 0.000 < 0.05, and has significant difference.

Animal experiments prove that the treatment effect of the experimental group is better than that of the control group.

The urethral stent is prepared by the method, and animal experiments are carried out on the urethral stent:

changes in the expression levels of PCNA, bcl-2 in the sectioned tissues were examined by the immunohistochemical SP method.

The specimen is selected from normal urethra segment and urethra scar segment, and the length of scar segment is 1cm after the experimental group and the control group are drawn for 1 month.

After being cut, the sections were fixed with 10% by volume of formaldehyde solution, embedded in paraffin, and sliced continuously with a thickness of 1 mm.

Dewaxing the slices conventionally, eliminating endogenous peroxidase by using hydrogen peroxide with the volume fraction of 3%, sealing normal sheep serum after antigen restoration, sequentially adding primary antibody and secondary antibody, performing DAB color development, performing hematoxylin counterstain, and sealing and observing.

PCNA positive expressing cells were obtained when the nucleus contained brown yellow particles, bcl-2 positive expressing cells were obtained when the cytoplasm contained yellow or brown yellow particles, as shown in Table 2.

TABLE 2

As can be seen from Table 2, a large number of PCNA and bcl-2 positively expressed cells were found in the scar tissue, and significant differences were observed compared with the normal urethra (P < 0.05). After the experimental group and the control group are drawn for 1 month, the urethral stricture rate of the experimental group is obviously different from that of the control group, and the urethral stricture rate of the experimental group is obviously smaller than that of the control group; in addition, a large number of PCNA and bcl-2 positive expression cells can be seen in the control group, and the significant difference is obtained compared with the experimental group.

Comparative example 1

The difference from example 1 is only that the particle size of the drug is 500 mesh, and the rest of the composition and the preparation method are the same as example 1.

The physical properties of the comparative example stent were tested according to the test method of example 1, and it was found that: the hardness of the stent matrix was 78A.

The support force of the stent was tested using a radial support dynamometer with a 10% compression force value of 108N.

The content of the drug components in the sample is calculated according to the weight, the drug dissolution tester is used for dissolving the drug in a simulated urine solution at 37 ℃, and the HPLC is used for testing the amount of the dissolved drug, so that the maximum drug dissolution amount in the first 7 days is 60 mug/d within 30 days, the maximum drug dissolution amount in the later 7 days gradually becomes stable and slow, and the average release degree in the 30 days is 12 mug/d.

As is clear from comparison between example 1 and comparative example 1, the lower the mesh number of the drug, the larger the particle size of the drug, and the lower the amount of drug released.

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 physical properties of the comparative example stent were tested according to the test method of example 1, and it was found that: the hardness of the stent matrix was 82A.

The support force of the stent was tested using a radial support dynamometer with a 10% compression force value of 105N.

The content of the drug components in the sample is calculated according to the weight, the drug dissolution tester is used for dissolving the drug in a simulated urine solution at 37 ℃, and the HPLC is used for testing the amount of the dissolved drug, so that the maximum drug dissolution amount in the first 7 days is 479 mug/d, the maximum drug dissolution amount in the later 7 days gradually becomes stable and slow, and the average release degree in the 30 days is 213 mug/d.

As is clear from the comparison between example 1 and comparative example 2, the higher the mesh number of the drug, the smaller the particle size of the drug and the higher the amount of drug released.

Comparative example 3

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

The physical properties of the comparative example stent were tested according to the test method of example 1, and it was found that: the hardness of the stent matrix is 60A.

The support force of the holder was tested using a radial support dynamometer with a 10% compression force value of 83N.

The content of the drug components in the sample is calculated according to the weight, the drug dissolution tester is used for dissolving the drug in a simulated urine solution at 37 ℃, and the HPLC is used for testing the amount of the dissolved drug, so that the maximum drug dissolution amount in the first 7 days is 305 mug/d within 30 days, the maximum drug dissolution amount in the later 7 days gradually becomes stable and slow, and the average release degree in the 30 days is 118 mug/d.

It is understood from a comparison between example 1 and comparative example 3 that a low crosslinking density increases the amount of drug released and decreases the hardness of the stent matrix.

Comparative example 4

The only difference from example 1 is that the cross-linking density of the silicone rubber is 10000g/mol, and the rest of the composition and the preparation method are the same as example 1.

The physical properties of the comparative example stent were tested according to the test method of example 1, and it was found that: the hardness of the stent matrix was 92A.

The support force of the stent was tested using a radial support dynamometer with a 10% compression force value of 136N.

The content of the drug components in the sample is calculated according to the weight, the drug dissolution tester is used for dissolving the drug in a simulated urine solution at 37 ℃, and the HPLC is used for testing the amount of the dissolved drug, so that the maximum drug dissolution amount in the first 7 days is 72 mug/d, the maximum drug dissolution amount in the later 7 days is gradually and steadily reduced within 30 days, and the average release degree within 30 days is 11 mug/d.

As is clear from a comparison between example 1 and comparative example 4, a high crosslinking density reduces the amount of drug released and increases the hardness of the stent matrix.

Example 2

The embodiment provides a stent, which comprises a stent matrix and a drug containing glucocorticoid dispersed in the stent matrix, wherein the stent matrix is made of caprolactone-lactide copolymer, and the drug containing glucocorticoid is budesonide.

The embodiment provides a preparation method of a stent, which comprises the following steps: dissolving 20 parts by weight of degradable material (caprolactone-lactide copolymer) and 1.5 parts by weight of medicine (budesonide) containing glucocorticoid in 50ml of acetone, adding 2 parts by weight of water-soluble polymer (cellulose, the cellulose is firstly dissolved in 5ml of water and then added into acetone solution) for mixing, removing the solvent, and heating and shaping to obtain the stent.

The support force of the holder was tested using a radial support dynamometer with a 10% compression force value of 92N.

Calculating the content of the drug components in the sample according to the weight, carrying out drug dissolution and degradation experiments on the sample in a simulated urine solution at 37 ℃ by using a drug dissolution tester, testing the amount of the dissolved drug by using HPLC, wherein the average release degree is 73 mug/d within 30 days; taking out the bracket at 7 days to test the radial supporting force, wherein the force value of 10% compression is 51N, and the mass loss is 12%; the stent is taken out for 30 days to test the radial supporting force, the force value of 10 percent of compression is 13N, and the mass loss is 82 percent.

Example 3

The embodiment provides a stent, which comprises a stent matrix and a drug containing glucocorticoid dispersed in the stent matrix, wherein the stent matrix is made of polyglycolic acid, and the drug containing glucocorticoid is mometasone furoate.

The embodiment provides a preparation method of a stent, which comprises the following steps: mixing 80 parts by weight of degradable material (polyglycolic acid), 5 parts by weight of medicament (mometasone furoate) containing glucocorticoid and 10 parts by weight of water-soluble polymer (chitosan) uniformly under melting condition (140 ℃), and extruding and shaping to obtain the stent.

The support force of the stent was tested using a radial support dynamometer with a 10% compression force value of 103N.

Calculating the content of the drug components in the sample according to the weight, carrying out drug dissolution and degradation experiments on the sample in a simulated urine solution at 37 ℃ by using a drug dissolution tester, testing the amount of the dissolved drug by using HPLC, wherein the average release degree is 61 mug/d within 30 days; taking out the bracket at 7 days to test the radial supporting force, wherein the force value of 10% compression is 58N, and the mass loss is 20%; the stent is taken out for 30 days to test the radial supporting force, the force value of 10 percent of compression is 9N, and the mass loss is 88 percent.

Example 4

The embodiment provides a stent, which comprises a stent matrix and a drug coating layer coated on the outer surface of the stent matrix and containing a glucocorticoid drug, wherein the stent is made of polyurethane, and the thickness of the drug coating layer containing the glucocorticoid drug is 0.2 mm.

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

(1) mixing 2 parts by weight of biodegradable high polymer material (polycaprolactone), 0.2 part by weight of polymer (polylactic acid) with long degradation period and 0.1 part by weight of medicine (mometasone furoate) containing glucocorticoid in 50mL of acetone to obtain mixed solution;

(2) performing melt extrusion molding on polyurethane to obtain a support matrix;

(3) treating the support matrix obtained in the step (2) with plasma for 30s, atomizing the mixed liquid obtained in the step (1) into particles with the particle size of 50nm-500 microns by using tooling equipment, uniformly spraying the particles on the outer surface of the treated support matrix, adopting air blowing for semi-drying in the spraying process, and drying in a drying oven at 40 ℃ after the spraying is finished to completely volatilize the solvent to obtain the support.

The support force of the stent was tested using a radial support dynamometer with a 10% compression force value of 113N.

The content of the drug in the sample is calculated according to the weight, a drug dissolution test is carried out on the sample in a simulated urine solution at 37 ℃ by using a drug dissolution tester, the amount of the dissolved drug is tested by HPLC, the maximum drug dissolution amount in the first 7 days is 273 mug/d, the total release amount in the first 7 days is 1396 mug, and the average release degree in the 30 days is 92 mug/d.

The ureteral stent with the specification of 8F is prepared by the method, the same animal experiment as that in example 1 is carried out on the ureteral stent, when 2 female New Zealand rabbits are implanted and then pulled out of the tube for one month, the average stenosis rate of an experimental group is 11.54 +/-1.58%, the stenosis degree of a control group is 21.8 +/-11.8%, P is 0.024 < 0.05, and the significant difference exists; after the tube is pulled out for 1 month, the stenosis degree of the experimental group is 6.09 +/-3.54 percent, the stenosis degree of the control group is 22.1 +/-19.1 percent, the P is 0.029 and is less than 0.05, and the significant difference exists.

Dissecting after 1 month of tube drawing, taking tissue slices, analyzing by using Image-Pro Plus 6.0 software, selecting 8 sections of each slice, and measuring the damage depth of the tissue. The depth of the injury in the experimental group is 1470 +/-173 mu m, the depth of the injury in the control group is 1777 +/-139 mu m, and P is 0.034 < 0.05, and the significant difference exists.

Tissue sections were taken, stained and the area percent of collagen fibers was measured using Image-pro plus 6.0 analytical software, with the area percent of collagen fibers for the experimental group being 46.75 + -2.59% and the area percent of collagen fibers for the control group being 69.96 + -3.88%. P is 0.000 < 0.05, and has significant difference.

Example 5

The embodiment provides a stent, which comprises a stent matrix and a drug coating coated on the outer surface of the stent matrix and containing a glucocorticoid drug, wherein the stent is made of silicon rubber, and the thickness of the drug coating containing the glucocorticoid drug is 0.3 mm.

(1) uniformly mixing 30 parts by weight of silicon rubber (RTV-2), 10 parts by weight of micronized drug (dexamethasone with the particle size of 3000 meshes) containing glucocorticoid, 0.6 part by weight of cross-linking agent (hydroxyl silicone oil) and 0.6 part by weight of catalyst (platinum) to obtain a mixture;

(2) processing and shaping 60 parts by weight of silicon rubber (RTV-2) through extrusion to obtain a support matrix;

(3) and (3) placing the mixed material obtained in the step (1) and the support matrix obtained in the step (2) into a mold, and curing (the curing temperature is 100 ℃, the curing pressure is 13MPa, and the curing time is 10min) to obtain the support.

The physical properties of the stent of this example were tested according to the test method of example 1, and it was found that: the hardness of the stent matrix was 86A.

The content of the drug components in the sample is calculated according to the weight, the sample is subjected to drug dissolution in a simulated urine solution at 37 ℃ by using 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 7 days is 118 mug/d within 30 days, and the average release degree in 30 days is 76 mug/d.

Example 6

The embodiment provides a stent, which comprises a stent matrix and a drug coating coated on the outer surface of the stent matrix and containing a glucocorticoid drug, wherein the stent is made of nickel-titanium alloy wires, and the thickness of the drug coating containing the glucocorticoid drug is 0.1 mm.

(1) uniformly mixing 25 parts by weight of heat-vulcanized two-component silicone rubber A (Dow Corning), 6 parts by weight of micronized drug (dexamethasone with the particle size of 6000 meshes) containing glucocorticoid and 1.5 parts by weight of catalyst (type 5000PPM, from Eucalyptus globulus) to obtain a mixture; uniformly mixing 25 parts by weight of heat-vulcanized two-component silicone rubber B (Doukonin), 6 parts by weight of micronized drug (dexamethasone with the particle size of 6000 meshes) containing glucocorticoid and 1.5 parts by weight of cross-linking agent (model PMX-0930, sourced Doukonin); uniformly mixing the mixed medicine-containing A/B in equal amount, and curing in a mold (curing temperature is 106 deg.C, curing pressure is 13MPa, and curing time is 20min) to obtain a medicinal film;

(2) weaving and shaping the nickel-titanium alloy wires to obtain a stent matrix;

(3) and (3) sticking the medicine film obtained in the step (1) and the stent matrix obtained in the step (2) together by adopting silicon rubber (Wake E41) to obtain the stent.

The support force of the stent was tested using a radial support dynamometer with a 10% compression value of 73N.

The content of the drug component in the sample is calculated according to the weight, the drug dissolution tester is used for dissolving the drug in a simulated urine solution at 37 ℃, the amount of the dissolved drug is tested by HPLC, and the maximum amount of the drug dissolved in the first 7 days is 296 mug/d within 30 days, and the average release degree is 97 mug/d.

Example 7

The difference from the embodiment 1 is that the outer surface of the stent also comprises a controlled release layer, the controlled release layer is made of silicon rubber, the cross-linking density of the silicon rubber is 1000g/mol, and the thickness of the controlled release layer is 0.02 mm.

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

(1) uniformly mixing silicon rubber, and extruding into a tubular shape to obtain a sleeve controlled release layer with the thickness of 0.02 mm;

(2) and (2) splitting the silicone rubber sleeve controlled release layer obtained in the step (1) along an axial line, coating the adhesive, sleeving the coated silicone rubber sleeve controlled release layer on the support prepared in the embodiment 1, and heating and fixing for 5min to obtain the support in the embodiment.

The support force of the stent was tested using a radial support dynamometer with a 10% compression force value of 112N.

The content of the drug ingredients in the sample is calculated according to the weight, the sample is subjected to drug dissolution in a simulated urine solution at 37 ℃ by using 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 7 days is 89 mug/d, the total drug release amount in the first 7 days is 796 mug, and the average release degree in the 30 days is 71 mug/d within 30 days.

Example 8

The difference from the embodiment 1 is that the outer surface of the stent also comprises a controlled release layer, the controlled release layer is made of silicon rubber, the cross-linking density of the silicon rubber is 6000g/mol, and the thickness of the controlled release layer is 0.2 mm.

(1) uniformly mixing silicon rubber, and extruding into a tubular shape to obtain a sleeve controlled release layer with the thickness of 0.2 mm;

The support force of the stent was tested using a radial support dynamometer with a 10% compression value of 128N.

The content of the drug ingredients in the sample is calculated according to the weight, the sample is subjected to drug dissolution in a simulated urine solution at 37 ℃ by using a drug dissolution tester, and the amount of the dissolved drug is tested by using HPLC, so that the maximum drug dissolution amount in the first 7 days is 16 mug/d, the total drug release amount in the first 7 days is 166 mug, and the average release degree in the 30 days is 65 mug/d.

Example 9

The difference from the embodiment 1 is that the outer surface of the stent is also provided with a hydrophilic coating, the material of the hydrophilic coating is polyvinylpyrrolidone, and the thickness of the hydrophilic coating is 0.03 mm.

(1) the mixed solution of polyvinylpyrrolidone was sprayed on the outer surface of the stent obtained in example 1, and the stent in this example was obtained by ultraviolet crosslinking and curing.

The physical properties of the stent of this example were tested according to the test method of example 1, and it was found that: the hardness of the stent was 80A.

The content of the drug ingredients in the sample is calculated according to the weight, the sample is subjected to drug dissolution in a simulated urine solution at 37 ℃ by using a drug dissolution tester, and the amount of the dissolved drug is tested by using HPLC, so that the maximum drug dissolution amount in the first 7 days is 5 mug/d, the total drug release amount in the first 7 days is 37 mug, and the average release degree in the 30 days is 53 mug/d.

Animal experiments of ureteral stents were carried out according to the method of example 1, the stents of example 1 and the stents of this example were randomly implanted, and after 1 month of extubation, the degree of urethral stricture was measured by radiography, with significant differences of 12.94 ± 2.02% in the group of example 1, 9.84 ± 2.70% in the group of this example, and 0.01 < 0.05 in P; after 1 month of tube drawing, the stenosis degree of the group in example 1 is 7.00 +/-4.57%, the stenosis degree of the group in this example is 2.64 +/-2.54%, and P is 0.019 < 0.05, which has significant difference.

Dissecting after 1 month of tube drawing, taking tissue slices, analyzing by using Image-Pro Plus 6.0 software, selecting 8 sections of each slice, and measuring the damage depth of the tissue. The depth of the damage of the group of example 1 is 1554 +/-115 mu m, the depth of the damage of the group of example is 1316 +/-134 mu m, and P is 0.001 < 0.05, and the significant difference exists.

Tissue sections were taken, stained, and the area percentage of collagen fibers was measured using Image-pro plus 6.0 analysis software, with the area percentage of collagen fibers being 51.78 + -5.96% in the example 1 group and 40.69 + -5.43% in the example group. P is 0.000 < 0.05, and has significant difference.

Animal experiments prove that the treatment effect of the group of the embodiment is better than that of the group of the embodiment 1.

Example 10

The difference from the embodiment 4 is that the outer surface of the drug coating is further provided with a hydrophilic coating, the material of the hydrophilic coating is maleic acid, and the thickness of the hydrophilic coating is 0.02 mm.

(1) the mixed solution of maleic acid was sprayed on the outer surface of the drug coating of the stent obtained in example 4, and the stent in this example was obtained by ultraviolet crosslinking and curing.

The support force of the stent was tested using a radial support dynamometer with a 10% compression value of 119N.

The content of the drug ingredients in the sample is calculated according to the weight, the sample is subjected to drug dissolution in a simulated urine solution at 37 ℃ by using a drug dissolution tester, and the amount of the dissolved drug is tested by using HPLC, so that the maximum drug dissolution amount in the first 7 days is 3 mug/d, the total drug release amount in the first 7 days is 41 mug, and the average release degree in the 30 days is 62 mug/d.

The ureteral stent with the specification of 8F is prepared by the method, the same animal experiment as that of the example 1 is carried out on the ureteral stent, when 2 female New Zealand rabbits are implanted for one month and then pulled out, the average stenosis rate of an experimental group is 11.06 +/-1.06%, the stenosis degree of a control group is 21.8 +/-11.8%, P is 0.019 < 0.05, and the significant difference exists; after the tube is pulled out for 1 month, the stenosis degree of the experimental group is 5.79 +/-3.09%, the stenosis degree of the control group is 22.1 +/-19.1%, the P is less than 0.026 and less than 0.05, and the significant difference exists.

Dissecting after 1 month of tube drawing, taking tissue slices, analyzing by using Image-Pro Plus 6.0 software, selecting 8 sections of each slice, and measuring the damage depth of the tissue. The depth of the injury of the experimental group is 1291 +/-122 mu m, the depth of the injury of the control group is 1777 +/-139 mu m, the P is 0.002 < 0.05, and the significant difference exists.

Tissue sections were taken, stained and the area percent of collagen fibers was measured using Image-pro plus 6.0 analytical software, with the area percent of collagen fibers for the experimental group being 47.99 + -5.73% and the area percent of collagen fibers for the control group being 69.96 + -3.88%. The P is 0.002 < 0.05, and has significant difference.

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. A stent for use in a urinary tract, the stent comprising a stent base and a drug disposed on the stent base.

2. The stent of claim 1, wherein the stent comprises a ureteral stent and/or a urethral stent;

preferably, the ureteral stent comprises any one of a single J-tube, a double J-tube or a straight tube;

preferably, the urethral stent comprises any one of a single-lumen catheter, a double-lumen catheter or a three-lumen catheter;

preferably, the urethral stent comprises a urethral stent with a balloon or a urethral stent without a balloon.

3. A stent according to claim 1 or 2, wherein the drug loading of a single stent is from 30 μ g to 200 mg;

preferably, a single said stent releases a dose of 5 μ g to 2mg per day;

preferably, the release period of the drug of a single stent is 5 to 90 days;

preferably, the drug of a single stent is not released or the amount released is less than 1mg 1h to 7 days after the complete implantation of the stent.

4. The stent of any one of claims 1-3, wherein the drug comprises a drug comprising a glucocorticoid;

preferably, the glucocorticoid-containing drug comprises any one or a combination of at least two of clobetasol, amcinonide, triamcinolone acetonide, tranilast, budesonide, mometasone furoate, dexamethasone, betamethasone, flumethasone, fluorometholone, hydrocortisone base, rimexolone, desoximetasone, cotylolone, prednisone ester, triamcinolone, rofleponide, ciclesonide, prednisone, cortisone or triamcinolone;

preferably, the medicament further comprises an anti-infective medicament comprising any one or a combination of at least two of beta lactams, macrolides, quinolones, aminoglycosides, antiviral agents or antifungal agents.

5. The stent according to any one of claims 1 to 4, wherein the stent matrix is made of degradable material and/or non-degradable material;

preferably, the degradable material comprises any one or a combination of at least two of polylactide, polylactide-glycolide, polyglycolide, polyglycolic acid/polylactic acid copolymer, polyethylene glycol, polycaprolactone, polyorthoester, polyglycolic acid, polybutylene succinate, caprolactone-lactide copolymer or polyhydroxyalkanoate;

preferably, the non-degradable material comprises any one or a combination of at least two of rubber, silicone rubber, polyester, polyvinyl chloride, polyurethane or metal;

preferably, the hardness of the stent matrix is 60-99A.

6. The stent of any one of claims 1-5, wherein the drug is dispersed within the stent matrix;

preferably, the particle size of the medicament is 800-12500 meshes;

preferably, the material of the stent matrix is silicon rubber, and the stent comprises 45-90% of silicon rubber, 5-50% of medicine, 0.1-3% of cross-linking agent and 0.1-3% of catalyst in percentage by mass;

preferably, the cross-linking density of the silicon rubber is 1000-8000 g/mol;

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

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

preferably, the preparation method of the scaffold comprises the following steps: and mixing the silicon rubber, the medicine, the cross-linking agent and the catalyst, and carrying out vulcanization and cross-linking to obtain the stent.

7. The stent according to any one of claims 1 to 6, wherein the stent matrix is made of degradable material, and the stent comprises 49 to 95 percent of degradable material, 4 to 50 percent of drug and optionally 1 to 20 percent of water-soluble polymer by mass percentage;

preferably, the water-soluble polymer comprises any one or a combination of at least two of chitosan, gelatin, acacia, hyaluronic acid, cellulose and derivatives thereof, polyacrylamide, polyacrylic acid, polyvinylpyrrolidone, polyvinyl acid, polymaleic anhydride, polyquaternium or starch;

preferably, the preparation method of the stent comprises the following steps: mixing a degradable material, a drug and an optional water-soluble polymer under a melting condition, and performing extrusion molding to obtain the stent;

preferably, the preparation method of the stent comprises the following steps: mixing degradable materials, medicines and optional water-soluble polymers in a solvent, removing the solvent, and heating and shaping to obtain the stent.

8. The stent of any one of claims 1-7, wherein the drug is dispersed on the outer surface of the stent matrix to form a drug coating on the outer surface of the stent matrix;

preferably, the drug coating is disposed on the outer surface of the stent substrate in a coated or wrapped manner;

preferably, the coating mode comprises any one of dipping, spinning, spraying or brushing, and further preferably spraying;

preferably, the drug coating has a thickness of 0.01-1 mm;

preferably, the stent base body comprises two opposite ends, wherein one end of the stent base body is an inlet end for introducing urine, the other end of the stent base body is an outlet end for leading out urine, and the thickness of the drug coating of the inlet end is larger than that of the drug coating of the outlet end;

preferably, the preparation method of the stent comprises the following steps: dissolving 40-98% of biodegradable high polymer material and 2-60% of medicine in a solvent to obtain a mixed solution; coating the mixed solution on the outer surface of a bracket matrix to form the bracket;

preferably, the mixed liquid is atomized into particles by using an atomizing device and then coated on the outer surface of the bracket substrate;

preferably, the particles are coated on the outer surface of the stent matrix in a wet or semi-dry state;

preferably, the particle size of the microparticles is 50nm to 500 μm, preferably 500nm to 200 μm;

preferably, the biodegradable polymer material comprises any one or a combination of at least two of gelatin, starch, hyaluronic acid, cellulose, chitosan, polylactic acid, polyglycolic acid, polycaprolactone, polylactide-caprolactone or polylactic acid-caprolactone;

preferably, the mixed solution further comprises a polymer with a long degradation period or which is not degradable, the mass percentage of the polymer with the long degradation period or which is not degradable is 0.5-10%, the mass percentage of the biodegradable high polymer material is 40-95%, and the mass percentage of the drug is 2-50%;

preferably, the polymer with long degradation period comprises any one or a combination of at least two of polylactic acid, polyglycolic acid, a blend containing polyglycolic acid, a polyglycolic acid copolymer or polyvinyl alcohol;

preferably, the non-degradable polymer comprises any one of polyvinylpyrrolidone, parylene, silicone oil, silicone gel, silicone rubber or polyethylene glycol or a combination of at least two of the same;

preferably, before the coating, the preparation method of the stent further comprises the steps of treating the outer surface of the stent matrix in advance;

preferably, the treatment manner comprises any one of plasma treatment, swelling treatment, sand blasting treatment, sanding treatment, dermatoglyph treatment, electrostatic treatment or wetting treatment or a combination of at least two of the treatments;

preferably, the preparation method of the stent comprises the following steps: mixing 24-80% of silicon rubber, 18-70% of micronized drug, 0.1-3% of cross-linking agent and 0.1-3% of catalyst by mass percentage to obtain a mixture, and then curing and combining the mixture and a stent matrix to obtain the stent;

preferably, the preparation method of the stent comprises the following steps: mixing 24-80% of silicon rubber, 18-70% of micronized drug, 0.1-3% of cross-linking agent and 0.1-3% of catalyst in percentage by mass to obtain a mixture, curing the mixture to obtain a drug membrane, and then combining the drug membrane and a stent matrix together in a secondary curing or gluing manner to obtain the stent;

preferably, the particle size of the micronized drug is 800-12500 meshes;

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

9. A stent according to any one of claims 1 to 8, wherein a controlled release layer and/or a hydrophilic coating is further provided on the outer surface of the stent matrix or on the outer surface of the drug coating;

preferably, the thickness of the controlled release layer is 0.01-1 mm;

preferably, the material of the controlled release layer is silicon rubber;

preferably, the cross-linking density of the silicon rubber is 1000-8000 g/mol;

preferably, the thickness of the hydrophilic coating is 0.01-0.5 mm;

preferably, the material of the hydrophilic coating is any one or a combination of at least two of polyethylene oxide, polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, polyisocyanate, sodium hyaluronate and maleic acid;

preferably, the outer surface of the stent comprises both a controlled release layer disposed on the outer surface of the stent substrate or the outer surface of the drug coating layer and a hydrophilic coating layer disposed on the outer surface of the controlled release layer.

10. Use of a stent according to any one of claims 1 to 9 in the manufacture of a drug delivery system.